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| #1TRPV4 neuromuscular disease registry highlights bulbar, skeletal and proximal limb manifestationsKosmanopoulos 2025 Read the full analysis | In a multicenter registry of 68 patients with pathogenic TRPV4 variants, disease was motor-predominant with frequent non-length-dependent proximal weakness, vocal fold weakness (55%) and skeletal involvement, and subclinical sensory loss was common on examination. Onset was bimodal, with 54% of questionnaire respondents reporting onset within the first 2 years. Proximal arm weakness did not discriminate CMT2C from SPSMA. Infantile-onset patients reported less sensory involvement and showed little correlation between age and CMTES. Because the data are largely cross-sectional, partly self-reported and probably subject to ascertainment bias, estimates of progression remain provisional. | Researchers collected information on 68 people with disease-causing changes in the TRPV4 gene, including people with CMT2C. Weakness, especially in the legs and sometimes in muscles near the hips and shoulders, was more common than numbness, although doctors often found reduced feeling when they tested for it. Just over half reported weakness of the vocal folds (the voice box muscles), and just as many reported shortness of breath. Spine and foot problems were common. Most people were seen only once and were volunteers, so how quickly the condition changes is still not clear. | Scientists checked 68 people who have a change in the TRPV4 gene. Many had weak legs, a weak voice, trouble breathing, a curved back, or feet with an unusual shape. Most people were only seen once, so nobody knows yet exactly how fast it changes. |
| #2Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2CLandouré 2010 Read the full analysis | Linkage analysis in two autosomal dominant CMT2C kindreds (LOD 3.1 and 6.9) mapped the disease to a 2.6 Mb interval on chromosome 12q24, where sequencing identified heterozygous TRPV4 missense variants at the same conserved ankyrin repeat domain residue (R269C, R269H), absent from 209 controls. In heterologous expression systems the mutants showed gain of function, with raised basal and stimulated currents without increased surface expression, and caused TRPV4-dependent cell death that channel inhibitors prevented. Phenotypic expression was highly variable within families, and two carriers appeared unaffected on limited home examination. | The researchers studied two big families with CMT2C and tracked the illness to a small stretch of chromosome 12. There they found a spelling change in the TRPV4 gene, at the same spot in both families. When they put the changed gene into cells grown in the lab, the channel it makes let in more calcium than normal and many cells died. How badly people were affected varied a lot, even between a mother and her daughter. | TRPV4 is like a door that lets calcium into cells. In two families with CMT2C, the gene for this door had a small mistake that left the door open too much, at least in cells grown in a dish. People in the same family could be affected in very different ways. |
| #3Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4Deng 2010 Read the full analysis | Sequencing of the shared 12q24 linkage interval identified heterozygous TRPV4 missense mutations in the ankyrin repeat-containing region, R316C in a large SPSMA family and R269H in a large CMT2C family. Each co-segregated with disease in the affected members tested and was absent from over 600 and over 700 controls, respectively, establishing SPSMA and CMT2C as allelic. In transiently transfected HEK293 cells both mutants trafficked to the plasma membrane and showed higher basal and stimulated calcium than wild type, and R269H gave a larger ruthenium red-sensitive conductance, suggesting gain of function. The family phenotyping and penetrance are not reported here. | The researchers studied two large families, one with SPSMA and one with CMT2C, and found that both conditions come from changes in the same gene, TRPV4. Each family had its own change, found in every affected relative whose DNA was tested but not in hundreds of unrelated control samples. When they put the changed gene into kidney cells grown in the lab, the channel let in more calcium than normal. The paper does not describe how healthy-looking relatives were checked. | Two families with different nerve and muscle illnesses turned out to have small mistakes in the same gene, TRPV4. TRPV4 makes a door that lets calcium into cells, and in lab cells the faulty door let in more calcium than usual, like a door that does not close properly. |
| #4Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2CAuer-Grumbach 2010 Read the full analysis | Linkage in a large pedigree and sequencing across five families identified heterozygous TRPV4 missense variants (R269H, R315W, R316C) at conserved arginines in the ankyrin repeat domain, present in all affected individuals with congenital distal SMA, SPSMA or HMSN2C and absent from European controls. In HeLa cells the mutant channels showed cytoplasmic aggregation, reduced surface expression and reduced hypo-osmotic and 4αPDD-evoked responses, but co-expression with wild type gave a wild-type response. The authors favored haploinsufficiency while not excluding a dominant-negative interaction. | The researchers found that changes in the TRPV4 gene caused three related inherited nerve conditions, including CMT2C, in five families, and that the changes were missing in hundreds of healthy people. One large family had all three conditions, showing that the same gene change can look different in different relatives. In lab-grown cells (not nerve cells), the changed TRPV4 protein got stuck inside the cell and let in less calcium. But when normal and changed protein were mixed, the cells behaved normally, so how the change causes disease was left uncertain. | Scientists found that a change in the TRPV4 gene causes CMT2C and two similar illnesses, and that people in one family can be affected in different ways. TRPV4 makes a door that lets calcium into cells. In their lab cells, the changed doors got stuck inside instead of reaching the cell's surface. But the scientists were not sure this is what happens in real nerves. |
| #5The gene for HMSN2C maps to 12q23-24: a region of neuromuscular disordersKlein 2003 Read the full analysis | Genome-wide linkage analysis in a single large autosomal dominant HMSN2C kindred gave a maximal two-point LOD score of 4.73 and a multipoint LOD score of 5.17 at 12q24, and recombinant haplotypes narrowed the locus to about 5.0 cM at 12q23.3-24.21. No CAG expansion or point mutation was found in the ataxin-2 repeat. Expressivity was highly variable (NIS 8 to 164), and one clinically unaffected relative carried the disease haplotype, which raises but does not resolve the question of reduced penetrance. | The researchers studied one very large family with CMT2C to find which part of the DNA travels with the condition. Affected relatives shared the same stretch of chromosome 12, which narrowed the search to a small region, but the team did not find the gene itself. Severity varied hugely within the family, and many affected people had weakness of the voice box or breathing muscles. One relative who seemed unaffected carried the same stretch of DNA, but the paper gives no detail about that person. | Scientists studied the DNA of one big family with CMT2C, like detectives looking for the street where a missing gene lives. They found the right street on chromosome 12, but not the exact house. Some family members were very weak and others only had a croaky voice. |
| #6Autosomal Dominant TRPV4-Related DisordersMcCray 2014 Read the full analysis | TRPV4-related neuromuscular disease (CMT2C, SPSMA and CDSMA) is presented as an autosomal dominant, motor-predominant, often non-length-dependent neuropathy or neuronopathy spectrum with frequent laryngeal, respiratory, auditory and skeletal involvement. Penetrance is reduced and expressivity highly variable within and between families. Most neuromuscular variants are missense changes at conserved arginines on the ankyrin repeat domain, and the preponderance of evidence supports gain of channel function. TRPV4 antagonists rescue knock-in mouse models, but efficacy in patients has not been shown. | CMT2C and two related nerve conditions are caused by changes in the same gene, TRPV4, and are best thought of as one condition with many forms. It mainly weakens muscles, often including the shoulders, and commonly affects the voice box, breathing, hearing and spine. People with the same gene change, even in one family, can be affected very differently, and some carriers show few or no signs. The gene change seems to make a calcium channel too active; blocking it helped in mice, but this has not yet been shown in people. | TRPV4 is like a door that lets calcium into cells. In this condition the door seems to be stuck too far open, which can weaken muscles, the voice and breathing. People in the same family can be affected very differently, and medicines that close the door have so far only been tested in mice. |
| #7TRPV4 mutations causing mixed neuropathy and skeletal phenotypes result in severe gain of functionTaga 2022 Read the full analysis | A de novo, possibly mosaic TRPV4 R616G variant caused a congenital sensorimotor axonal neuropathy with bilateral vocal cord paralysis and no definite skeletal dysplasia, whereas R616Q at the same residue is reported in skeletal dysplasia. Review of 36 published mixed neuropathy and skeletal cases (19 variants) showed early mean onset and frequent progression but no definitive genotype-phenotype correlation. On heterologous expression, R616G and L619P produced marked constitutive calcium elevation, cytotoxicity and right-shifted GSK219 inhibition (IC50 216 and 198 nM versus 8 nM), which structural modeling attributed to S5 helix disruption. This suggests that the magnitude of gain of function may relate to severe or mixed phenotypes and to antagonist sensitivity. | The researchers describe a toddler with a new change in the TRPV4 gene who had severe nerve damage and paralyzed vocal cords, but no clear bone disease, even though a different change at the same spot is known to cause bone disease. They also gathered 36 published cases of people with both nerve and bone problems and found that these problems usually started in early childhood and often got worse. In lab-grown cells, the strongest changes let calcium in all the time, killed more cells and needed much more of a blocking compound to switch the channel off. This suggests that future drug trials may need to check the dose for each specific gene change. | TRPV4 is like a door that lets calcium into cells. With some gene changes the door is stuck wide open all the time, and in lab cells those doors did more harm and were harder to close with a door-blocking chemical. Some children with these changes have problems with both their nerves and their bones. |
| #8Incidence and Clinical Features of TRPV4-Linked Axonal Neuropathies in a USA Cohort of Charcot-Marie-Tooth Disease Type 2Deng 2020 Read the full analysis | Sanger sequencing of all 15 coding exons of TRPV4 in 62 genetically unexplained CMT2 probands identified two previously reported pathogenic variants, R316C and R269C, a yield of 3.2% (2/62), or 2.1% (2/96) of the full cohort; a third variant, I571M, was judged benign or of very low penetrance. Phenotypes were markedly variable and included vocal cord and phrenic nerve paralysis, scoliosis and high-frequency hearing loss, with electrophysiology consistent with an axonal neuropathy. Non-penetrance in three relatives is inferred from the pedigree without genotyping or documented examination, so no penetrance estimate can be drawn from this family. | The team checked the TRPV4 gene in 62 people with the nerve-fiber type of CMT (type 2) whose cause was unknown. Two of them had a TRPV4 change already known to cause disease. These two men, and relatives in one family, differed a lot: some had paralyzed vocal cords that weakened the voice or breathing, one had trouble hearing high-pitched sounds, and severity varied greatly. The paper says some relatives carry the change without symptoms, but those relatives were not tested and, as far as the paper says, not examined. | Scientists looked at one gene, TRPV4, in 62 people with a nerve illness called CMT and found a change in it in 2 of them. TRPV4 makes a tiny door that lets calcium into cells, and earlier studies suggest these changes leave the door open too much. Even in one family, the illness was very different from person to person. We cannot be sure that some relatives carry the change without being ill, because nobody checked them. |
| #9TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathiesKlein 2011 Read the full analysis | Sequencing of TRPV4 in 53 axonal CMT probands identified two heterozygous ankyrin repeat domain variants, R232C (segregating in a kindred in which only the proband had vocal cord paresis) and a de novo R316H, in 2 of 17 CMT2C families and none of 36 undifferentiated CMT2 cases. In transfected cells both mutants trafficked normally to the plasma membrane, raised basal intracellular calcium (HEK293) and increased cell death in HeLa cells, which ruthenium red prevented. The authors interpret this as a constitutive gain of function causing calcium cytotoxicity, while allowing that other factors may contribute. | The team checked the TRPV4 gene in 53 people with an inherited nerve disease of the CMT2 type and found changes in only two families, both with the CMT2C form. In one family a man had a paralyzed vocal cord, but his mother and sister, who carried the same change and had mild nerve damage on testing, did not. In another man the change was new and not inherited from his parents. In cells grown in the lab, the faulty channel let in extra calcium, and in one cell type more cells died unless the channel was blocked with a chemical. | TRPV4 is like a door that lets calcium into cells. In cells grown in a dish, the faulty doors found in two families let in too much calcium, and in one kind of cell this harmed the cells unless the doors were blocked. People in one family with the same faulty door had different symptoms. |
| #10Novel mutations highlight the key role of the ankyrin repeat domain in TRPV4-mediated neuropathySullivan 2015 Read the full analysis | Two novel heterozygous missense variants at the same residue, p.Arg237Gly and p.Arg237Leu, were identified in two unrelated CMT2C families and map to the convex face of the TRPV4 ankyrin repeat domain alongside other neuropathy-associated arginines. In transfected HEK293T and MN-1 cells both variants trafficked normally but raised basal intracellular Ca2+ and caused cytotoxicity that was abolished by the TRPV4 antagonist HC-067047, consistent with gain of function. A homology model suggests the convex face is accessible to as yet unidentified binding partners; segregation data are limited to two affected individuals per family. | The researchers found two new spelling changes in the TRPV4 gene, both at the same spot (position 237), in two families with CMT2C. This spot is in a part of the protein called the ankyrin repeat domain, where many other CMT2C changes are found. In cells grown in the lab, the changed channels let in too much calcium and more cells died, and a drug that blocks TRPV4 stopped this. Only four people were studied, and lab cells may not behave like human nerves. | TRPV4 is like a door that lets calcium into cells. In two families with CMT2C, the door had a change in the same small spot, and in lab cells that door let in too much calcium and harmed the cells. A blocker that shut the door helped the cells in the dish, but it was not tested in people. |
| #11Exome sequencing identifies a novel TRPV4 mutation in a CMT2C familyLandouré 2012 Read the full analysis | Exome sequencing in a CMT2C kindred previously negative on Sanger sequencing identified a novel heterozygous TRPV4 missense variant, c.557G>A (R186Q), segregating with disease (3 affected carriers, 6 unaffected non-carriers) and absent from 200 controls; SNPs under the original primers probably caused monoallelic amplification of the wild-type allele. R186 lies on the convex face of the ankyrin repeat domain with other neuropathy mutations. In transfected HEK293 cells, R186Q produced a modest basal calcium rise and increased cell death, both blocked by ruthenium red, which the authors interpret as increased constitutive (gain-of-function) activity. | In one family, three people had CMT2C, with weak hands and feet, a hoarse voice and noisy breathing. An older genetic test had missed the cause because the test's starting points sat on common, harmless DNA differences. A newer method that reads all genes found a new change in the TRPV4 gene in all three affected people, and in none of the six unaffected relatives or 200 unrelated people. In lab-grown cells, the changed channel let in a little more calcium and killed more cells, which suggests it is overactive. | TRPV4 is like a door that lets calcium into cells. Everyone in this family with the illness had the same tiny spelling change in the TRPV4 gene. In lab cells, the changed door seemed to let in a bit too much calcium and harmed the cells. The first test missed the change because it only read the healthy copy of the gene, like reading only one of two copies of a page. |
| #12CMT2C with vocal cord paresis associated with short stature and mutations in the TRPV4 geneChen 2010 Read the full analysis | Two autosomal dominant CMT2C kindreds carried heterozygous TRPV4 variants, the novel S542Y (transmembrane domain) and R315W, which were present in affected members, absent in available unaffected relatives and absent from 200 controls. Both showed motor-predominant axonal neuropathy with variable vocal cord paresis, from absent to tracheotomy-dependent, and family 1 had short stature more than 2 SD below population means, suggesting overlap with TRPV4 skeletal dysplasia. No TRPV4 variants were found in 20 familial CMT probands without vocal cord paresis. | The researchers studied two families with CMT2C, an inherited nerve condition that weakens muscles and can affect the vocal cords. Each family had its own change in the TRPV4 gene. Across the two families, vocal cord problems ranged from none to so severe that a permanent breathing opening in the neck (tracheotomy) was needed. In one family the affected women were on average much shorter than typical American women, which suggests the gene change may also affect bone growth, though this is based on few people. | Two families had a nerve illness called CMT2C, caused by changes in a gene called TRPV4. Some family members had weak voices or trouble breathing and others did not, and in one family many were quite short. The doctors think the gene might affect bones as well as nerves, but two families are not enough to be sure. |
| #13Reduced penetrance in hereditary motor neuropathy caused by TRPV4 Arg269Cys mutationBerciano 2011 Read the full analysis | In one pedigree with the heterozygous TRPV4 c.805C>T (p.Arg269Cys) variant, an ankyrin-region change, the two affected members showed strikingly different phenotypes: an adult facio-scapulo-peroneal motor neuropathy and a congenital distal SMA with arthrogryposis and vocal cord paresis, with electrophysiology indicating a length-dependent motor axonopathy. Three carriers aged 9, 40 and 70 had normal examination, nerve conduction, EMG and lower-leg MRI, which the authors interpret as non-penetrance. The evidence comes from a single family, and the authors note only two carriers were beyond the average age of onset. | This study looked at one family with a change in the TRPV4 gene called Arg269Cys. A mother had weakness in her face, shoulder blades and lower legs, while her daughter was born with stiff joints and had serious breathing and voice-box problems. Three other relatives carried the same change but showed no signs of nerve disease, even on careful nerve tests and muscle scans. The authors call this reduced penetrance, meaning some people with the change do not develop the condition, but this is based on one family. | TRPV4 is like a door that lets calcium into cells. In this family, five people had the same change in the instructions for the door, but only two were ill and three seemed completely well when doctors checked them. So the same gene change can affect people in very different ways. |
| #14Dominant mutations in the cation channel gene transient receptor potential vanilloid 4 cause an unusual spectrum of neuropathiesZimoń 2010 Read the full analysis | Sequencing of TRPV4 in 145 unrelated index patients with hereditary neuropathy, 83 of them selected for atypical features, identified five heterozygous missense mutations (including the novel Arg232Cys) in eight families, four of the five at strictly conserved arginines on the convex surface of the ankyrin repeat domain. Phenotypes ranged from congenital distal SMA and scapuloperoneal SMA to HMSN2C, distal HMN with vocal fold paresis and generic axonal HMSN2, with marked intra- and interfamilial variability and axonal electrophysiology in all patients studied. Six clinically unaffected carriers were taken to indicate reduced penetrance, but how these carriers were assessed is not described and some were young. | The researchers checked the TRPV4 gene in 145 people from Europe and the USA with inherited nerve disease and found changes in eight families. Even within one family, the illness could look very different from person to person: some were born with club feet or stiff joints, while others first had weakness as adults. Many had extra problems such as weakness of the vocal folds (in the voice box), hearing loss or a curved spine. Six relatives carried the gene change but were described as unaffected, which suggests not everyone with the change becomes ill. However, the paper does not say how carefully these relatives were checked. | TRPV4 is a gene that tells the body how to build a tiny door that lets calcium into cells. In eight families, a small spelling mistake in this gene caused nerve problems, but the problems were very different from one person to the next, even in the same family. A few relatives had the mistake but seemed well, though the paper does not say how closely they were checked. |
| #15Confirmation of a hereditary motor and sensory neuropathy IIC locus at chromosome 12q23-q24McEntagart 2005 Read the full analysis | Linkage analysis in two further families supported the CMT2C locus on chromosome 12q23-24 (combined multipoint LOD 2.1, below the conventional threshold of 3) and narrowed the interval to 3.9 Mb containing 66 genes; ataxin-2 was excluded by sequencing. Clinically, onset ranged from birth to 62 with marked intrafamilial variability, two members developed respiratory failure requiring bi-level ventilatory support, and asymptomatic relatives had signs of axonal neuropathy on examination and nerve conduction studies. | Researchers studied two more families with CMT2C to check where on our chromosomes the faulty gene lay. Both families pointed to the same part of chromosome 12, though the statistical result was supportive rather than conclusive on its own. The search area shrank to 66 genes. The age when symptoms began ranged from birth to 62, two people needed machines to help them breathe, and some relatives who felt fine had signs of the condition when examined and tested. | Scientists were looking for where the CMT2C gene hides, like narrowing down which street a house is on. Two more families pointed to the same neighborhood on chromosome 12. In these families some people were affected as babies and others only as older adults. Some relatives who felt well still showed small signs when a doctor checked their nerves. |
| #16A TRPV4 mutation caused Charcot-Marie-Tooth disease type 2C with scapuloperoneal muscular atrophy overlap syndrome and scapuloperoneal spinal muscular atrophy in one family: a case report and literature reviewChen 2023 Read the full analysis | This report describes a Chinese father and son heterozygous for TRPV4 p.R316C with discordant phenotypes: the father had a sensorimotor axonal neuropathy with scapuloperoneal atrophy (labeled CMT2C and scapuloperoneal muscular atrophy overlap) and a sural biopsy showing severe myelinated fiber loss with regenerating clusters and pseudo-onion bulbs. The son had congenital clubfoot, chronic neurogenic EMG changes and an absent fibular CMAP without weakness (labeled early SPSMA). The authors use this, with a literature review, to illustrate intrafamilial variability. The father's long-standing diabetes is a possible contributor to his sensory and biopsy findings that the paper does not address. | A father and son in China both carry the same TRPV4 change, but their illness looks different. The father, aged 58, has weak and wasted muscles around the shoulders and legs and lost feeling in his hands and feet; a sample of his leg nerve showed many lost nerve fibers. His 27-year-old son was born with a clubfoot and has no weakness, but nerve tests show early signs of nerve damage. The father also has long-standing diabetes, which can affect nerves, and the paper does not discuss this. | A dad and his son have the same small mistake in the TRPV4 gene. The dad has weak muscles and numb feet, while the son only had a twisted foot at birth and some changes on nerve tests. It shows the same mistake can look different in different people in one family. The dad also has diabetes, which can hurt nerves too, so not all of his problems may come from TRPV4. |
| #17Charcot-Marie-Tooth disease type 2C and scapuloperoneal muscular atrophy overlap syndrome in a patient with the R232C TRPV4 mutationKoutsis 2015 Read the full analysis | A 43-year-old woman heterozygous for TRPV4 p.R232C had childhood-onset, slowly progressive weakness with vocal cord paresis, diaphragmatic paralysis, scapular winging and scoliosis, consistent with a CMT2C and SPMA overlap syndrome. Nerve conduction studies showed a purely motor axonal neuropathy at 20 and a severe sensorimotor axonal neuropathy at 43, which the authors interpret as a possible phenotypic shift. A heterozygous sister was reported as clinically and electrophysiologically unaffected, which the authors take as evidence of reduced penetrance, although supporting details are not provided. | This letter describes one Greek woman with the TRPV4 change R232C. Her problems started in childhood and slowly got worse. She had weak legs and shoulders, a weak voice box and a paralyzed breathing muscle, and needed a wheelchair by 40. Her nerve tests showed only movement nerves affected at 20, but feeling nerves were affected too by 43. Her sister has the same gene change but was described as having no signs, which suggests the change does not always cause illness. However, few details about the sister are given. | This is the story of one woman whose TRPV4 gene change made her muscles, voice and breathing weak. Her illness slowly changed over the years. Her sister has the same gene change but seemed well, a bit like two houses with the same faulty door where only one has noticed a problem so far. |
| #18Severe Multifocal Noninfectious Wound Dehiscence After Cavovarus Reconstruction in TRPV4-Associated Charcot-Marie-Tooth Disease Type 2C: A Case ReportElhaddad 2026 Read the full analysis | A 10-year-old girl with CMT2C due to TRPV4 c.806G>A (p.Arg269His) developed multifocal, culture-negative wound dehiscence within weeks of extensive cavovarus reconstruction that the authors considered technically appropriate. The wounds healed after serial debridement, negative-pressure wound therapy and a biodegradable temporizing matrix, with complete healing at 15 months. A qualitative fibroblast explant culture showed delayed outgrowth and reduced early adherence compared with one control. The authors raise the hypothesis of a TRPV4-related wound-healing vulnerability but state that a single case cannot establish causality. | This report describes one girl with CMT2C who had major surgery to straighten a very stiff, turned-in foot. Within weeks, several of her surgical cuts opened up, even though there was no infection. With months of specialist wound care everything healed, and 15 months later her foot was flat and stable. Skin cells grown from her in a lab spread out more slowly than cells from one comparison sample. The surgeons wonder whether her TRPV4 change makes healing harder, but one case cannot prove this. | A girl with CMT2C had a big operation on her foot, and her cuts opened up afterward even though there were no germs. After a lot of careful treatment, her foot healed well. The doctors wonder if her TRPV4 change made healing harder, but with only one person they cannot tell for sure. |
| #19Remediation of Perceptual Deficits in Progressive Auditory Neuropathy: A Case StudyRance 2024 Read the full analysis | Longitudinal assessment of a child with a heterozygous TRPV4 R316H variant and a motor-predominant axonal neuropathy showed stable normal pure-tone thresholds but a progressive decline in ABR wave V amplitude and worsening gap detection, consistent with a progressive auditory neuropathy. Binaural (spatially separated) speech-in-noise perception deteriorated over the first 18 months and returned to normal after fitting of a remote-microphone system, with improvement reported even in unaided testing. The authors attribute this to neuroplasticity, but as a single uncontrolled case the cause of the improvement and its generalizability to CMT2C remain uncertain. | This study followed the hearing of one boy with CMT2C over a 3-year period. On a standard hearing test he could hear quiet sounds normally. But recordings from the hearing nerve got weaker, and he found it harder to pick out speech in background noise, which suggests the hearing nerve itself was being affected. A small microphone worn by his teacher, sending their voice straight to his ear, helped a lot, and the researchers report his listening in noise later improved even without it. Because this is only one child with no comparison group, we cannot be sure why he improved or whether the same would happen for others. | This boy could hear quiet sounds well. But the nerve that carries sound to his brain slowly worked less well, a bit like a phone line getting crackly, so voices got muddled when it was noisy. A special microphone that sent his teacher's voice straight to his ear helped him understand. But he is only one boy, so we do not know if it would work the same for everyone. |
| #20Case of Charcot-Marie-Tooth Type 2C Due to a TRPV4 Gene Mutation With Isolated Sudomotor Autonomic DysfunctionBaker 2018 Read the full analysis | In a single patient with TRPV4-related CMT2C, quantitative sweat testing showed markedly reduced sweat output at all four sites, while heart rate responses to deep breathing and Valsalva and the response to head-up tilt were normal, indicating isolated sudomotor dysfunction. The authors propose a link to TRPV4's role as a warmth-activated channel involved in temperature regulation, based largely on rodent data. As a single case, it shows the feature can occur but not its frequency or cause. | Doctors tested the nerves that control sweating, heart rate and blood pressure in one woman with CMT2C. She made almost no sweat at any of the four places tested, but her heart rate and blood pressure responses were normal. She had a lot of trouble staying cool. The authors think the TRPV4 channel, which responds to warmth, may be involved, but this idea comes mostly from animal studies. | One woman with CMT2C hardly sweated at all, so she got too hot easily, a bit like a car whose cooling system is not working. The parts of her body that control her heartbeat and blood pressure were fine. Because this is only one person, we do not know how many people with CMT2C have this. |
| #21Striking phenotypic variability in familial TRPV4-axonal neuropathy spectrum disorderAharoni 2011 Read the full analysis | In a single family, five heterozygous carriers of the ankyrin repeat TRPV4 variant R315W showed striking intrafamilial variability, from bilateral vocal cord paralysis requiring tracheostomy to a 14-year-old with an essentially normal examination, consistent with variable expressivity and possibly reduced penetrance. The proband's phenotype evolved from motor to sensorimotor axonal neuropathy on repeat testing, and skeletal deformities were attributed to weakness rather than primary dysplasia. Non-penetrance in this family is not firmly established, because the apparently unaffected carrier was young and declined nerve conduction studies. | Five people in one family carry the same TRPV4 change, R315W, but are affected very differently. Two children needed a breathing tube in the neck because their vocal cords did not move, while a 14-year-old brother plays sports and had an almost normal examination. He did not have nerve tests and is still young, so it is not certain he will stay unaffected. The authors say families should know that severity can vary a lot. | Think of TRPV4 as a door that lets calcium into cells. In this family everyone with the same faulty door was affected differently: some children needed help to breathe, while one brother plays sports and seems fine for now. Doctors cannot yet tell who will be more or less affected. |
| #22TRPV4 axonal neuropathy spectrum disorderMcEntagart 2012 Read the full analysis | This review characterizes the TRPV4 axonal neuropathy spectrum as a predominantly motor axonal neuropathy, frequently with vocal cord paralysis and occasionally with sensorineural hearing loss and bladder urgency and incontinence, inherited in an autosomal dominant manner with variable expressivity and reduced penetrance. It also covers neuropathy and skeletal dysplasia overlap disorders and the effects of mutations on channel function. The supporting evidence cannot be judged from the abstract. | This article reviews nerve conditions caused by TRPV4 changes, which mainly weaken muscles through damage to the motor nerves. Many people also have weak or paralyzed vocal cords, and some have hearing loss or bladder urgency. The condition passes from parent to child, its severity varies, and some people with the change may show few or no signs. | A change in the TRPV4 gene can make the nerves to the muscles and the voice box weak. It can run in families, and it can be strong in one person and hardly noticeable in another. |
| #23Charcot-Marie-Tooth disease type 2C: a distinct genetic entity. Clinical and molecular characterization of the first European familySantoro 2002 Read the full analysis | In the first European family reported with CMT2C, linkage to the CMT2A, B, D, E and F loci and to the distal hereditary motor neuronopathy type VII locus was excluded, supporting CMT2C as a genetically distinct entity. The disease showed high penetrance and variable expressivity, with apparently more severe limb involvement in the youngest generation, and vocal cord paralysis did not correlate with limb weakness. Family size and assessment methods are not given in the abstract. | Doctors described the first European family known to have CMT2C, a type of CMT that can affect the vocal cords and the breathing muscles. Genetic tests showed the condition was not linked to any of the CMT2 gene regions known at the time, so it was a separate condition. Most people who inherited it showed signs, severity varied, and how weak someone's vocal cords were did not match how weak their arms and legs were. | In one family, many people had CMT2C, and it affected each of them differently. Some had a weak voice because their vocal cords did not move well, even when their arms and legs were not very weak. For others it was the other way round. |
| #24Clinical, laboratory, and genetic studies of families with Charcot-Marie-Tooth type 2C diseaseLandoure 2011 Read the full analysis | Linkage of two of five CMT2C families to 12q24.11 and sequencing of the interval identified heterozygous TRPV4 missense mutations R269C and R269H, with R186Q, R232C and a variant of uncertain significance (D584N) found subsequently; one family excluded the locus, indicating genetic heterogeneity. The neuropathy residues lie in the intracellular N-terminal ankyrin repeat domain, on the opposite face from skeletal dysplasia mutations. R269C and R269H trafficked normally but increased cytotoxicity and constitutive and activated currents, consistent with gain of function. Methods and data cannot be assessed from the abstract. | This PhD research studied five families with CMT2C. In two of them the condition was traced to a stretch of chromosome 12, where changes in the TRPV4 gene were found. In one other family, the condition did not trace back to that region, so CMT2C may have more than one cause. In lab-grown cells, two of the TRPV4 changes made the channel pass more current and harmed the cells. The nerve-disease changes sat on a different side of one part of the protein from changes that cause bone disease. | TRPV4 is like a door that lets calcium into cells. This research found that in some families with CMT2C the door has a small fault. In lab cells, the faulty door let through more calcium than normal and hurt the cells. One family's illness did not seem to come from this door. |
| #25Hereditary motor and sensory neuropathy with diaphragm and vocal cord paresisDyck 1994 Read the full analysis | Dyck and colleagues described two autosomal dominant kindreds with an axonal hereditary motor and sensory neuropathy featuring variable limb, vocal cord and intercostal weakness and asymptomatic sensory loss, onset in infancy or childhood in severe cases, and reduced life expectancy from respiratory failure in severely affected patients. Normal conduction velocities placed it within HMSN II, and they designated it HMSN IIc. Linkage to the HMSN IA (17p) and IB (1q) loci was not demonstrated in one large pedigree. | This 1994 paper is the first description of the condition now called CMT2C. In two families, it caused weakness in the arms and legs, the vocal cords and the muscles used for breathing, and how severe this was varied a lot between people. Some people had lost feeling without noticing it. In the most severely affected, it started in childhood and breathing failure shortened their lives. Nerve signal speeds were normal, which showed the nerve fibers themselves (the axons) were affected, so the authors named it HMSN IIc. | This is the first paper about CMT2C. Doctors met two families where the condition made arms, legs, voice and breathing muscles weak, more in some people than others. Some people had lost a little feeling without knowing, like a smoke alarm with a quiet battery that only a tester notices. |
| #26Varying occurrence of vocal cord paralysis in a family with autosomal dominant hereditary motor and sensory neuropathyDonaghy 1999 Read the full analysis | In a British family with autosomal dominant axonal HMSN, the proband developed recurrent laryngeal nerve palsy at 41 years with an abducens palsy, while the mother and sister had electrophysiologically confirmed but asymptomatic polyneuropathy. The authors interpret this as the second HMSN IIC kindred, notable for adult-onset laryngeal involvement, and argue for clinical and electrophysiological screening of first-degree relatives. No molecular confirmation was available. | Doctors described a British family where one person lost the use of a vocal cord nerve at age 41, after having nerve symptoms in the limbs for 4 years. Their mother and sister felt completely fine, but nerve tests (which measure how well signals travel along the nerves) showed they had the same nerve condition. The doctors concluded that close relatives should be examined and tested, because feeling well does not prove someone is unaffected. | One person in a family had a weak voice from an inherited nerve condition, probably CMT2C. Their mom and sister felt fine, but a nerve test showed they had it too, like a car that drives well but whose check-up still finds a fault. |
| #27Comprehensive analysis of the TRPV4 gene in a large series of inherited neuropathies and controlsFawcett 2012 Read the full analysis | In 422 patients with CMT2 or dHMN negative for common genes, TRPV4 sequencing found five novel variants absent from controls, of which only G20R, N302Y and T701I were considered potentially pathogenic, giving a TRPV4 mutation frequency of less than 1%. Pathogenicity was not established functionally or by segregation. The nonsense variant Y567X caused nonsense-mediated decay without reducing lymphoblast TRPV4 protein, from which the authors infer that haploinsufficiency is not sufficient to cause neuropathy and that TRPV4 harbors many rare benign variants. | The researchers checked the TRPV4 gene in 422 people with inherited nerve disease whose cause had not been found. Less than 1% had a TRPV4 change that might cause disease, and even those changes were not proven to be harmful. Some rare TRPV4 changes, including one that cuts the protein short, seemed to be harmless, so the authors say new TRPV4 changes must be checked carefully before patients are told. | Scientists checked TRPV4, the instructions for a tiny gate in our cells, in 422 people with nerve problems. Only a very few had a change that might cause trouble, and some changes looked like harmless typos, like a spelling slip that does not change what a sentence means. |
| #28Hereditary motor and sensory neuropathy type 2C is genetically distinct from types 2B and 2DNagamatsu 2000 Read the full analysis | In a large autosomal dominant HMSN 2C kindred (12 affected, 11 at risk), two-point and multipoint linkage analysis excluded the HMSN 2B (3q13-q22) and HMSN 2D (7p14) loci, with multipoint LOD scores below -2 across both regions under a model of 0.99 penetrance and no phenocopies. Together with earlier exclusion of HMSN 2A, the authors infer at least 4 genetically distinct autosomal dominant HMSN 2 types. The HMSN 2C locus itself was not mapped. | The researchers studied one large family with CMT2C, an inherited nerve disease that can also weaken the vocal cords and the main breathing muscle (the diaphragm). They tested whether the disease was passed down together with two stretches of DNA already linked to other types of CMT2. It was not, so the CMT2C gene had to be somewhere else in the genome. This study did not find where. | Scientists were looking for the gene behind one family's nerve illness, a bit like hunting for a lost key in a big house. They searched two rooms where keys for similar illnesses had been found, and the key was not there. They still had to search the rest of the house. |
| #29TRPV4 disrupts mitochondrial transport and causes axonal degeneration via a CaMKII-dependent elevation of intracellular Ca2Woolums 2020 Read the full analysis | Expression of human TRPV4 R269C in Drosophila neurons caused dose-dependent, pore-dependent neuronal dysfunction and axonal and dendritic degeneration, consistent with a gain-of-function mechanism, and the antagonist GSK2193874 reduced degeneration. A modifier screen identified CaMKII as required for R269C-induced hyperexcitability, Ca2+ elevation and toxicity, and CaMKII inhibition reduced TRPV4-mediated Ca2+ responses in cultured mouse trigeminal neurons. R269C impaired axonal mitochondrial transport before degeneration, and toxicity was modulated by Miro in a Ca2+-binding-dependent manner; all data come from overexpression models. | The researchers put a human TRPV4 gene carrying a neuropathy mutation into fruit flies and into mouse nerve cells in a dish. The faulty channel let in too much calcium, made nerve cells overactive, slowed the movement of mitochondria (the cell's power stations) along nerve fibers, and damaged the fibers. Blocking TRPV4 with a drug, or turning down an enzyme called CaMKII, reduced the damage in flies, but this has not been tested in people. | TRPV4 is like a door that lets calcium into nerve cells, and this mutation makes the door open too easily. In flies, too much calcium jammed the delivery trucks that carry power packs along the nerve. A medicine that closes the door helped the fly nerves, but it has not been tried in people. |
| #30Neuropathy-causing TRPV4 mutations disrupt TRPV4-RhoA interactions and impair neurite extensionMcCray 2021 Read the full analysis | The TRPV4 ankyrin repeat domain binds inactive, GDP-bound RhoA directly, and this binding mutually restrains TRPV4 channel activity and RhoA activation. Neuropathy mutations at surface arginines of the ARD (R232C, R237L, R269C, R315W) nearly abolish the interaction independently of channel activity, whereas skeletal dysplasia mutations (I331F, D333G) show variably preserved binding. Loss of binding plus calcium-driven RhoA activation impairs neurite outgrowth in MN-1 cells, and dominant-negative Rho1 rescues axonal and dendritic degeneration in a Drosophila model expressing TRPV4 R269C. All data come from cell lines, purified proteins and flies. | TRPV4 is a channel on the surface of cells. This study found that it holds on to another protein, RhoA, which controls the cell's internal scaffolding. The TRPV4 mutations that cause nerve disease stop TRPV4 from holding RhoA, so RhoA becomes too active and the nerve-like branches of cells grown in dishes do not grow properly. In flies carrying a human TRPV4 neuropathy mutation, blocking the fly version of RhoA protected their nerve fibers. This was all done in cells and flies, so it is not yet known whether the same happens in people. | Think of TRPV4 as a door in a nerve cell that also holds the leash of a dog called RhoA, which can pull the cell's branches back in. The CMT2C changes make the door drop the leash, so RhoA pulls too much and the branches stay short. Calming RhoA helped in flies, but this has not been tested in people. |
| #31TRPV4-Rho GTPase complex structures reveal mechanisms of gating and diseaseKwon 2023 Read the full analysis | Cryo-EM structures of full-length human TRPV4 co-purified with RhoA (3.30 to 3.75 Å) show membrane-anchored RhoA bound to ankyrin repeats AR2 to AR5 of each subunit, restraining the rigid-body rotation of the ankyrin repeat domain that accompanies ligand-dependent gating. Most neuropathy residues (R237, R269, R315, R316) lie at this interface, and interface mutations in either protein reduced binding and increased TRPV4-mediated calcium influx in cell lines, supporting loss of RhoA-mediated inhibition as a mechanism for gain of function. Agonists and the clinical antagonist GSK279 share a binding pocket in the voltage-sensor-like domain that does not overlap known disease mutations. | TRPV4 is a channel on the surface of the cell that lets calcium in. Using a very powerful microscope, the researchers saw that another protein, RhoA, grips the inner part of TRPV4 and seems to stop it from opening too easily. Many of the gene changes that cause TRPV4 nerve disease sit exactly where RhoA grips, and breaking this grip in lab-grown cells made the channel let in more calcium. They also saw where a TRPV4-blocking drug attaches, which could help design medicines, but this was not tested in CMT2C. | Think of TRPV4 as a door that lets calcium into a cell, and RhoA as a hand that holds the door partly shut. In CMT2C, the mistakes in the door seem to be right where the hand holds on, so the door may swing open too much. This was seen in lab experiments, not yet in people. |
| #32Profiling the TRPV4 ankyrin repeat domain interactome and its disruption by neuromuscular disease-causing mutationsLoder 2026 Read the full analysis | Using a human proteome microarray, the authors identified 78 candidate binding partners of the wild-type TRPV4 ankyrin repeat domain, 21 of which were not detected with the neuromuscular disease mutants R269C and R315W but were retained with the skeletal dysplasia mutant D333G. In transfected MN-1 cells, ARHGEF10 co-immunoprecipitated less with the mutants, and ARHGEF10 overexpression suppressed wild-type but not mutant TRPV4-mediated calcium responses, suggesting that loss of an inhibitory interaction may contribute to the gain of function. These are cell-free and overexpression findings that need confirmation in native tissue. | The TRPV4 channel has a region called the ankyrin repeat domain that works like a handle other proteins can grab. Researchers tested which of more than 17,000 human proteins grab this handle and found 78 likely partners. Disease-causing changes seen in TRPV4 nerve and muscle conditions seemed to stop 21 of them from grabbing on. One partner, ARHGEF10, appeared to calm the normal channel but could not calm the disease versions, although this was only shown in cells grown in the lab. | TRPV4 is like a door that lets calcium into cells, and it has a handle that helper proteins can hold to stop the door from opening too much. Scientists found that with the disease versions, some helpers, such as one called ARHGEF10, may not hold on as well. This was seen in lab dishes, not in people. |
| #33Mutant TRPV4-mediated toxicity is linked to increased constitutive function in axonal neuropathiesFecto 2011 Read the full analysis | In three transiently transfected cell lines (HEK293, HeLa, Neuro2a), R269H, R315W and R316C TRPV4 trafficked to the plasma membrane and produced higher basal and 4αPDD-evoked calcium and more cell death than wild type, effects blocked by ruthenium red. In HeLa cells, R269H increased ruthenium red-sensitive current density and single-channel open probability without changing single-channel conductance, consistent with altered gating and possibly greater membrane insertion. The authors conclude that these neuropathy mutations act by gain of function, a conclusion drawn from overexpression in cell lines only. | TRPV4 is a channel that lets calcium into cells. Earlier studies disagreed about whether disease-causing changes make it work too much or too little. In three types of lab-grown cells, this team found that three known changes made the channel open more often, let in more calcium and killed more cells, and that a channel-blocking chemical prevented this. This supports the idea that the changes make the channel overactive, but it was tested only in lab cell lines. | Think of TRPV4 as a door for calcium. In cells in a dish, the faulty doors stayed open more often than normal doors and let in too much calcium, which harmed the cells. A chemical that blocks the door stopped the harm, but only in the dish. |
| #34Structural and biochemical consequences of disease-causing mutations in the ankyrin repeat domain of the human TRPV4 channelInada 2012 Read the full analysis | Crystal structures of the human TRPV4 ankyrin repeat domain with and without ATP show that ligand binding mainly alters the flexible Finger 3 loop, and thermal denaturation, cysteine accessibility and steered molecular dynamics (partly on TRPV1) indicate that ATP stabilizes the domain. Neuropathy-associated arginine substitutions map to the convex face, whereas skeletal dysplasia mutations lie mainly on the concave face. Most of 13 disease mutants reduced domain thermal stability and some altered ATP binding, but neither property segregated with neuropathy versus skeletal phenotype, implying additional regulatory mechanisms. | The TRPV4 channel has a section called the ankyrin repeat domain, which sits inside the cell and helps control how the channel behaves. The researchers made this section in bacteria and worked out its 3D shape, with and without ATP, a small molecule that fine-tunes the channel. Changes that cause nerve disease sit on one face of this section, and bone-disease changes mostly sit on the other. Most changes made the section less stable when heated, and some changed how it held ATP, but neither result explained why some changes affect nerves and others affect bones. | TRPV4 is like a door that lets calcium into cells, and this study looked at the door's handle on the inside. The scientists mapped where nerve-disease and bone-disease changes sit on the handle, but they still could not tell why some changes hurt nerves and others hurt bones. |
| #35TRPV4 channel activity is modulated by direct interaction of the ankyrin domain to PI(4,5)P2Takahashi 2014 Read the full analysis | The TRPV4 ankyrin repeat domain binds phosphoinositides, preferentially PI(4,5)P2, at a site defined by a 1.9 Å crystal structure of the chicken ARD with IP3, and PI(4,5)P2 binding suppresses channel activity in HEK293 cells. The disease mutations R269H, R315W and R316H destabilized the ARD, lost PI(4,5)P2 binding and sensitivity, and showed gain-of-function currents and increased cell death, whereas R232C retained PI(4,5)P2 sensitivity. Whether loss of PI(4,5)P2 regulation, rather than instability-driven changes in other interactions, causes the gain of function remains unresolved. | TRPV4 has a section called the ankyrin domain that sits just inside the cell. This study found that this section sticks to a fat in the cell membrane called PI(4,5)P2, and that this contact keeps the channel's activity down. Three CMT2C and SMA mutations made the section unstable, stopped it from sticking and left the channel more active. Another mutation (R232C) worked differently. All tests were done in lab-grown kidney-derived cells, not nerves. | TRPV4 is like a door that lets calcium into a cell, and it has a handle that normally hooks onto the wall to stop the door from opening too much. Some CMT2C changes seem to make the handle wobbly so it cannot hook on, and the door opens too easily, at least in cells grown in a lab. |
| #36The impact of TRPV4 pathogenic mutations on barrier integritySampaio 2025 Read the full analysis | In ECIS impedance assays, pharmacological TRPV4 activation (GSK101) disrupted HUVEC barriers, an effect that partial CRISPR knockdown or the inhibitor ABS-0872 prevented. Transient expression of all 51 ClinVar pathogenic or likely pathogenic TRPV4 variants in ARPE-19 cells raised basal calcium for 47 of 51, but disrupted the barrier only for 7 of 22 peripheral neuropathy variants (mostly in the ankyrin repeat domain), 8 of 13 metatropic dysplasia variants and no other skeletal dysplasia variants, with no correlation between basal activity and disruption. ABS-0872 inhibited the mutant channels and prevented, or with early dosing reversed, barrier loss in vitro; the authors, all company employees, describe the genotype-phenotype correlation as weak. | Cells that line blood vessels, and some other cells, hold tightly together to form a seal. In lab-grown cells, switching TRPV4 on weakened this seal, and so did the CMT2C change R269C. When the team tested all 51 known disease-causing TRPV4 changes in an eye cell line, almost all made the channel let in extra calcium. But only some weakened the seal: 7 of 22 nerve disease changes, most changes behind one severe bone condition (metatropic dysplasia), and none of the other bone disease changes. The experimental blocker ABS-0872, made by the company that ran the study, protected the seal and helped it recover in these cells, but it was not tested in animals or people in this paper. | TRPV4 is like a door that lets calcium into cells. Cells in a dish normally hold hands tightly to make a wall. With some faulty doors stuck open, the cells let go a little and the wall became leaky. A new medicine that partly closes the door helped them hold on again. This was only in cells in a dish, not in people. |
| #37Combined clinical, structural and cellular studies discriminate pathogenic and benign TRPV4 variantsBerth 2025 Read the full analysis | In heterologous overexpression assays, known pathogenic TRPV4 variants consistently showed gain of function (raised basal and hypotonic-evoked calcium and increased cytotoxicity). Gain-of-function variants clustered at charged ankyrin repeat domain residues at the RhoA interface and in the central intrinsically disordered region (S93F, S94L, P97R), where the P97R effect depended on PIP2 binding; transmembrane domain variants and ankyrin repeat domain variants away from the RhoA interface showed normal or reduced function and were classed as likely benign. Adding the functional data changed the ACMG class for 9 of 19 clinical variants. In a small number of patients, gain of function was associated with congenital onset, vocal cord weakness and motor-predominant disease, but the approach assumes gain of function is the disease mechanism and was not validated against known benign variants. | TRPV4 is a channel in the cell surface that lets calcium in. The researchers put 30 different TRPV4 changes into cells grown in the lab and checked whether each made the channel overactive and harmful to the cells. Known disease-causing changes made it overactive; many changes of uncertain meaning did not, so the team judged them probably harmless. People whose changes made the channel overactive tended to have problems from birth, a weak voice box or mainly muscle weakness, but this pattern comes from only a handful of patients and from lab cells, not nerves. | TRPV4 is like a door that lets calcium into cells. The scientists tested many small spelling mistakes in the TRPV4 instructions. They found that the ones known to cause illness jam the door too far open. Many others leave the door working normally and are probably harmless. They tested this in cells in a dish and in only a few people, so it is a helpful guide rather than a final answer. |
| #38Multiubiquitination of TRPV4 reduces channel activity independent of surface localizationAisenberg 2022 Read the full analysis | TRPV4 is multiubiquitinated predominantly within its N- and C-terminal intrinsically disordered regions, and N-terminal IDR ubiquitination negatively regulates channel activity without altering plasma membrane abundance, partly via PIP2 binding. The neuropathy mutant R269C showed reduced ubiquitination in HEK293T cells and Drosophila; ubiquitination was restored by an antagonist or a pore-inactivating mutation, indicating that the reduction is secondary to gain of function. NEDD4 overexpression partially suppressed R269C and R237L overactivity in cell lines. | Cells can stick tiny tags called ubiquitin onto proteins to change how they work. This study found that these tags on one end of TRPV4 act like a brake, reducing how much calcium the channel lets in, without removing the channel from the cell surface. A CMT2C-causing change (R269C) had fewer tags, seemingly because the channel was already overactive. Adding more tags with an enzyme called NEDD4 partly calmed the faulty channel in lab-grown cells. | TRPV4 is a door that lets calcium into cells, and the cell can stick small tags on it that work like a brake. In CMT2C the door is stuck too far open and has fewer brake tags. Adding more tags helped close the door a little in lab cells, but nobody has tried this in people. |
| #39Structure of human TRPV4 in complex with GTPase RhoANadezhdin 2023 Read the full analysis | Cryo-EM structures of full-length human TRPV4 (about 3.0 Å) revealed endogenous GDP-bound RhoA attached to the membrane-facing surface of the ankyrin repeat domain, with interface residues (R232, R237, D263, R269, R315, R316) that largely coincide with disease-causing mutation sites. An interface substitution, R316A, increased baseline calcium uptake, consistent with RhoA acting as an inhibitor. The agonist 4α-PDD and antagonist HC-067047 both bind at the base of the S1-S4 bundle, with agonist binding opening the pore and inhibition involving a π-to-α transition in S6; the neuropathy link is inferred from mapping rather than tested with patient variants here. | Using a powerful electron microscope, researchers made a detailed 3D picture of the human TRPV4 channel. They found a protein called RhoA, which can reduce TRPV4 activity, stuck to the channel's ankyrin region. The exact spots where RhoA touches TRPV4 are mostly places where disease-causing changes have been found, including changes linked to neuropathy. They also showed where an opening drug and a blocking drug attach, which may help design medicines in the future. | TRPV4 is like a door that lets calcium into cells, and RhoA is like a hand that helps keep the door from opening too much. Scientists took a super-detailed picture and saw that the hand grips the door right where many disease changes are. That suggests these changes might loosen the grip, but this still needs testing. |
| #40Gain-of-function mutations of TRPV4 acting in endothelial cells drive blood-CNS barrier breakdown and motor neuron degeneration in miceSullivan 2024 Read the full analysis | In knock-in mice carrying the CMT2/dSMA-causing mutations R269C (homozygous) or R232C (heterozygous) in the endogenous Trpv4 gene, TRPV4 gain of function in neural vascular endothelial cells was associated with focal blood-spinal cord barrier breakdown in the upper cervical cord, loss of the tight junction protein ZO-1, regional motor neuron degeneration and early lethality. Deleting the mutant allele from endothelial cells (Cdh5Cre, Tie2Cre), but not from neurons, glia or muscle, rescued the phenotype, indicating a non-cell-autonomous mechanism. Systemic GSK2193874 started at symptom onset restored barrier integrity, protected C1 motor neurons and rescued survival in a dose-dependent manner in R269C mice. No human tissue was studied, and the mouse disease reflects only the severe end of the human spectrum. | TRPV4 is a channel, a kind of gate on the cell surface that lets calcium in. The researchers put two disease-causing TRPV4 changes into mice, which became weak, lost nerve cells at the top of the spinal cord and died young. The faulty channel worked too strongly in the cells lining small blood vessels, and this made the protective barrier between the blood and the spinal cord leak in patches next to motor neurons (the nerve cells that control muscles). Removing the faulty gene from those vessel cells, or injecting a TRPV4-blocking drug once symptoms began, stopped the leak and rescued the mice, but none of this has been tested in people. | TRPV4 is like a door that lets calcium into cells. In these mice, the door was stuck too far open in the walls of tiny blood vessels, so the vessels in the spinal cord leaked like a cracked pipe and nearby nerve cells got hurt. A medicine that pushes the door shut fixed the leak and helped the mice. But they were very sick young mice, and nobody knows yet whether the same thing happens in people or whether the medicine would help them. |
| #41Intrafamilial variable hearing loss in TRPV4 induced spinal muscular atrophyOonk 2014 Read the full analysis | In one family carrying the TRPV4 R269H variant in the fourth ankyrin repeat, all four heterozygous carriers had mild to moderate sensorineural hearing loss with differing audiometric configurations, and three with serial audiograms showed progression beyond age-related norms at different frequencies. Hearing severity did not correlate with the severity of the neuromuscular phenotype. With four carriers and a spinal muscular atrophy phenotype, the findings describe this family and cannot establish frequency or mechanism in CMT2C. | Researchers tested the hearing of a Dutch family with a TRPV4 change, R269H, which is also found in some people with CMT2C. All four relatives with the change had hearing loss coming from the inner ear or hearing nerve, first noticed between ages 35 and 62. In three of them, tests confirmed it got worse over time. The pattern differed between relatives, and how bad someone's hearing was did not match how bad their muscle weakness was. The family is small, so these are observations rather than rules. | Four people in one family had the same change in their TRPV4 gene, and all of them found their hearing slowly getting worse as grown-ups. It was like four radios with the same fault, each losing different sounds. How weak their legs were did not tell you how bad their hearing would be. |
| #42TRPV4 neuropathy-causing mutations localize to the convex face of the ankyrin repeat domain (reply in the Neurology correspondence “Phenotypic spectrum and incidence of TRPV4 mutations in patients with inherited axonal neuropathy”)Sullivan 2014 Read the full analysis | In correspondence on Echaniz-Laguna et al. (2014), Sullivan and colleagues state that TRPV4 Arg186Gln had already been reported, with its ankyrin repeat domain (ARD) location and cell-based functional effects. They also state that the mutated arginines (Arg186, Arg232, Arg269, Arg315 and Arg316) lie on the convex face of the ARD rather than the concave face, and argue that residue location bears on pathogenicity. The letter cites earlier crystal structures and reports but presents no new data. | This is a short letter from one research team to a journal about another team's paper on TRPV4 nerve disease. They say a mutation the other paper called new had already been described. They also disagree about where several CMT2C-linked mutations sit on one part of the TRPV4 protein, the ankyrin repeat domain: they say the mutations sit on the side that bulges outward, not the side that curves inward. They think this matters for understanding how the mutations cause disease. | Two teams of scientists disagreed about where the CMT2C changes sit on one part of the TRPV4 'door'. It is a bit like arguing whether a sticker is on the outside or the inside of a curved shell. This letter gives one team's side. |
| #43Phenotypic variability of TRPV4 related neuropathiesEvangelista 2015 Read the full analysis | Two unrelated patients with heterozygous TRPV4 missense variants had divergent phenotypes: a de novo p.Arg269Cys variant with an SPSMA-like neurogenic phenotype plus clinical features suggestive of skeletal dysplasia, and a novel N-terminal cytoplasmic domain variant, p.Asp62Asn, with a late-onset axonal neuropathy compatible with CMT2C. Pathogenicity of p.Asp62Asn rests on in silico prediction, population rarity and incomplete segregation data. Basophilic inclusions in one muscle biopsy led the authors to propose a protein-aggregation mechanism shared with heat shock protein neuropathies, which remains untested. | The authors describe two people with changes in the TRPV4 gene. A boy had muscle weakness from babyhood plus short stature and short fingers, while a woman developed foot and leg weakness at about 40, like CMT2C. The woman's gene change had not been described before, and the evidence that it causes her illness comes mainly from computer predictions and how rare it is. Clumps seen in her muscle sample led the authors to suggest how the damage might happen, but this is an idea, not a proven finding. | The TRPV4 gene is like the instructions for a door that lets calcium into cells. This paper describes two people with mistakes in those instructions who got quite different illnesses, one as a small child and one as a grown-up. The doctors have ideas about why, but they have not proven them yet. |
| #44Channelopathies converge on TRPV4Nilius 2010 Read the full analysis | This News and Views piece summarizes three 2010 linkage and sequencing studies showing that SPSMA and CMT2C are allelic disorders caused by heterozygous TRPV4 missense mutations (R269C, R269H, R315W, R316C), all in the ankyrin repeat region. It highlights conflicting functional data: no response and cytoplasmic retention in HeLa cells in one study, versus gain of function in HEK293 cells and Xenopus oocytes in the other two. The authors note that genotype-phenotype links are unclear and suggest TRPV4 as a possible therapeutic target, without presenting new data. | In 2010 three research teams found that changes in the TRPV4 gene cause CMT2C and a related condition called scapuloperoneal spinal muscular atrophy (SPSMA). This short commentary explains those findings. All the changes were in one part of the TRPV4 protein, the ankyrin repeat region, which is thought to help it connect with other proteins. The teams disagreed on whether the changes made the channel work too much or not at all, and the authors list this and other puzzles as open questions. | Three teams of scientists found that CMT2C is caused by small changes in a gene called TRPV4, which makes a door that lets calcium into cells. They did not yet agree on whether the changes leave the door stuck too far open or stuck shut. |
| #45Essential Tremor in a Charcot-Marie-Tooth Type 2C Kindred Does Not Segregate with the TRPV4 R269H MutationLouis 2014 Read the full analysis | In a CMT2C kindred carrying TRPV4 R269H, four relatives met research criteria for essential tremor, but R269H was found only in relatives with both CMT2C and ET and was absent from two relatives with ET alone. The authors conclude that tremor in this family is unlikely to reflect incomplete penetrance or variable expressivity of R269H and more likely represents co-occurring ET. The evidence comes from a single kindred with seven genotyped members, and the tremor in mutation carriers cannot be firmly attributed to one cause. | This family has CMT2C caused by a TRPV4 change called R269H, and several relatives also have a shaking of the hands called essential tremor. Two relatives with the tremor had neither the TRPV4 change nor CMT, so the tremor seems to run in the family separately from CMT2C. This study covers only one family, so it cannot say how often tremor in CMT2C has the same explanation. | In one family, some people had CMT2C and some had shaky hands. A few people had shaky hands without the CMT2C gene change, so the shaking seems to be a separate family trait. It is a bit like freckles and curly hair: they are passed down separately, even though some people get both. |
| #46Combined Phenotypes of Spondylometaphyseal Dysplasia-Kozlowski Type and Charcot-Marie-Tooth Disease Type 2C Secondary to a TRPV4 Pathogenic VariantFaye 2019 Read the full analysis | A woman with a de novo heterozygous TRPV4 c.943C>T (p.R315W) variant had radiographically defined spondylometaphyseal dysplasia Kozlowski type from early childhood and a progressive motor-greater-than-sensory axonal polyneuropathy diagnosed as CMT2C. She also carried a paternally inherited N302Y variant of uncertain significance whose contribution was not assessed. Drawing on prior reports, the authors argue that TRPV4 skeletal and neuromuscular phenotypes form an overlapping spectrum that is not predicted by variant domain alone. | This report describes one woman whose TRPV4 gene change caused both a bone growth condition affecting her spine and hips (a skeletal dysplasia) and CMT2C nerve disease. Her gene change was new in her, not passed on from her parents. The authors say TRPV4 bone and nerve conditions are not completely separate and can happen together, and they suggest checking for both. | TRPV4 is like a door that lets calcium into cells in both bones and nerves. In this one woman, a mistake in the door affected both her bones and her nerves. Doctors used to think these were separate illnesses, and this case adds to the idea that they can happen together. |
| #47The remarkable phenotypic variability of the p.Arg269HiS variant in the TRPV4 geneJędrzejowska 2019 Read the full analysis | In two Polish families, the TRPV4 R269H variant showed marked variability within and between families, from mild scapular winging to congenital contractures with skeletal involvement, and nocturnal non-invasive ventilation in one adult. Congenital arm contractures and cranial nerve signs were described with R269H for the first time. Across published R269H families, the same variant has been labeled CMT2C, scapuloperoneal SMA and congenital distal SMA. The authors find no anticipation, suggesting that modifiers influence severity, although the data are descriptive and partly based on family history. | Doctors in Poland describe two families with the same TRPV4 change, R269H. In one family a mother had only mild shoulder blade weakness into her fifties, while one daughter was born with stiff joints and has never walked without help, and an uncle uses a breathing machine at night. In earlier reports, the same change has been given three different diagnosis names, and the illness did not seem to start earlier in each new generation. The authors think other factors besides the gene change affect how severe it is. | In one Polish family, the same TRPV4 gene change affected each person differently: a mom was only a little affected, while her daughters were more affected. It is like the same recipe turning out differently each time it is baked. Doctors think something else, not just the gene change, also affects how strong the illness is. |
| #48De novo somatic mosaicisms of INF2 and TRPV4 in patients with Charcot-Marie-Tooth diseaseLee 2025 Read the full analysis | A girl with severe early-onset TRPV4 axonal neuropathy carried a de novo S729R variant, located near the TRP box outside the ankyrin repeat domain, at an estimated 30% somatic mosaic level in blood. Despite mosaicism, her phenotype was severe, including vocal cord paresis, hearing loss and a length-dependent pattern of fatty muscle replacement on MRI. The variant was classed as likely pathogenic on the basis of rarity, conservation and in silico prediction, without functional testing, and the mosaic level in nerve is unknown. | A Korean girl with severe CMT2C had a new change in the TRPV4 gene that was not inherited from either parent. Only about 30% of the DNA in her blood carried the change, which is called mosaicism, yet her disease was still severe. The researchers did not test the change in the lab and could only measure it in blood, not in nerves. | Our bodies are built from many tiny cells, like bricks in a wall. In this girl only some of the bricks had the TRPV4 change, but she was still very affected. She is only one person, so we cannot say this always happens. |
| #49Genetic heterogeneity in Charcot-Marie-Tooth neuropathy type 2Yoshioka 1996 Read the full analysis | Linkage analysis in a large CMT2C pedigree using markers from the CMT2A locus on the short arm of chromosome 1 found no evidence of linkage, indicating that CMT2C is not allelic to CMT2A. The result adds to evidence of genetic heterogeneity among inherited axonal neuropathies. Pedigree size, phenotyping and LOD scores cannot be assessed from the abstract. | Researchers checked whether CMT2C in one large family came from the same area of chromosome 1 as another type, CMT2A. It did not. This showed CMT2C is a separate genetic condition. | Scientists checked whether CMT2C came from the same spot in our DNA as another kind of CMT, and found it did not. So CMT2C has its own cause. |
| #50Long-Term Observations in an Affected Family with Neurogenic Scapuloperoneal Syndrome Caused by Mutation R269C in the TRPV4 GeneVill 2015 Read the full analysis | In a father and son heterozygous for TRPV4 R269C, phenotypes ranged from classical scapuloperoneal syndrome to severe neonatal onset with respiratory distress and arthrogryposis multiplex. Over two decades the father showed no relevant progression and the son improved to independent ambulation with orthoses by age 5, paralleled by stable or improved muscle ultrasound findings. Neurography showed a late-onset sensory neuropathy in the father. Prognostic conclusions rest on one family, and methods cannot be assessed from the abstract. | Doctors followed a father and son with the same TRPV4 change, R269C, for more than two decades. The father had weakness around the shoulder blades and lower legs that hardly changed, while the son was very ill at birth but improved a lot and was walking with leg braces by age 5. Later, nerve tests showed the father had also developed some damage to the nerves that carry feeling. | A dad and his son had the same TRPV4 change. The son was very sick as a baby but got much stronger and could walk with braces by age 5, and the dad stayed about the same for many years. |
| #51A case of congenital spinal muscular atrophy with pain due to a mutation in TRPV4Fleming 2016 Read the full analysis | A patient with congenital spinal muscular atrophy, pain, subjective sensory loss, talipes equinovarus and progressive gait impairment carried TRPV4 c.806G>A (Arg269His), although relatives reportedly had CMT1A. EMG showed an axonal motor neuropathy or neuronopathy. The authors propose skeletal radiography to identify orthopedic causes of pain and support a TRPV4 diagnosis, and electrodiagnostic confirmation even when a familial genotype is presumed. Clinical detail cannot be assessed from the abstract. | Doctors describe a person born with weakness from damaged motor nerve cells who also had pain and felt that their sensation was reduced. Relatives were said to have a different type of CMT, CMT1A, but nerve tests pointed elsewhere, and genetic testing showed this person had a TRPV4 change, Arg269His. The authors say X-rays can help find bone causes of pain, and that nerve tests are useful even when a family's diagnosis seems known. | One person with a TRPV4 change had weak legs and pain. Their relatives were thought to have a different kind of CMT, so checking this person's own nerves helped find the right answer, like checking a map instead of guessing the way. |
| #52Clinical and genetic heterogeneity in peroneal muscular atrophy associated with vocal cord weaknessMcEntagart 2002 Read the full analysis | Linkage analysis of chromosome 2q14 microsatellites spanning the DHMNVP locus gave negative two-point LOD scores in one HMSN IIC family and one family with distal weakness, vocal cord paralysis and sensorineural deafness. The authors conclude that dHMN-VII and HMSN IIC are unlikely to be allelic and that at least one further locus exists. | Before the CMT2C gene was found, researchers suspected it might be the same gene as a similar condition that also affects the vocal cords. They tested two families and found the condition did not travel with that part of chromosome 2, so the cause was probably a different gene. | Scientists were hunting for the CMT2C gene. They checked one hiding place on chromosome 2 and it was empty, which told them to look somewhere else. |
| #53Phenotypic spectrum and incidence of TRPV4 mutations in patients with inherited axonal neuropathyEchaniz-Laguna 2014 Read the full analysis | Screening of 169 French probands with axonal neuropathy found no pathogenic TRPV4 variants in 95 with pure dominant CMT2, but 12 of 74 (16%) with vocal cord paralysis and/or skeletal dysplasia carried one, most diagnosed as dHMN. Among 17 affected individuals, all had childhood-onset motor neuropathy with foot deformities, kyphoscoliosis and raised CK, and 94% had vocal cord paralysis. Six variants were de novo and 2 asymptomatic carriers were reported, with assessment methods not stated in the abstract. | French doctors tested 169 people with an axonal type of inherited neuropathy for TRPV4 changes. None of the 95 people with 'pure' CMT2 had one, but 12 of the 74 people who also had vocal cord paralysis or bone problems did. Almost all of the 17 people with a TRPV4 change had vocal cord paralysis, and all had weakness from childhood, foot shape changes and a curved spine. Two relatives carried the change without symptoms, but the abstract does not say how they were checked. | Doctors looked for the CMT2C gene change in 169 people. They only found it in people who also had a weak voice or bone problems. Those problems are like a clue that points detectives to the right suspect. |
| #54Whole-Body Muscle MRI in Non-5q Spinal Muscular Atrophy: Patterns, Genotype Prediction, and Diagnostic ImplicationsBerling 2026 Read the full analysis | In a retrospective cohort of 28 adults with non-5q SMA, whole-body muscle MRI (Mercuri grading, plus Dixon fat fraction in 21) identified reproducible gene-specific patterns for VRK1, DYNC1H1 and VWA1. The four TRPV4 patients showed heterogeneous involvement and poor concordance with previously published TRPV4 lower-limb patterns, but severe sternocleidomastoid involvement occurred in 2 of 4 and in no other cohort member. The authors propose this as a supportive but inconsistent marker requiring validation in larger cohorts. | The researchers looked at whole-body MRI scans of the muscles of 28 adults with a group of rare motor nerve conditions; 4 of them had TRPV4 changes. The scans show which muscles have been replaced by fat. For some genes there was a clear, repeatable pattern, but the scans of the 4 TRPV4 patients all looked different from each other. Two of them had heavy damage in a neck muscle that nobody else in the study had, which could be a clue worth testing in more people. | Doctors took pictures of all the muscles of 28 adults with weak muscles. The pictures of the 4 people with TRPV4 changes all looked different. But 2 of them had a weak neck muscle that nobody else had. That might be a clue, like a footprint, though only a few people were checked. |
| #55Hip Dysplasia in Charcot-Marie-Tooth Disease: Insights From a Large Cohort of Children and AdolescentsTan 2025 Read the full analysis | In a retrospective single-center cohort of 178 children with CMT and related neuropathies, radiographic hip dysplasia (migration percentage, acetabular index, lateral center edge angle) was present in 36.0% at first radiograph and 28.1% at last follow-up, with 9.6% requiring surgery. All 4 children with TRPV4-related CMT had hip dysplasia and 2 required surgery, but this subgroup is very small and selection for radiography was not systematic. The authors propose that TRPV4-related skeletal effects and non-ambulation may contribute, without multivariable analysis to test this. | This study looked back at hip X-rays of 178 children with CMT at one Australian hospital. 64 of them had a shallow or poorly fitting hip socket (hip dysplasia) on their first X-ray, often without any hip symptoms, and 17 needed an operation. All 4 children with the TRPV4 form of CMT had hip dysplasia, but 4 is too few to know how common this is in TRPV4 nerve disease. | The hip is a ball that sits in a cup. In some children with CMT the cup is too shallow, so the ball does not sit snugly. All 4 children in this study with the TRPV4 type had this, but that is only a few children, so we cannot be sure how often it happens. |
| #56Comparison of the natural course of clinical and radiologic features in 13 patients with TRPV4-related skeletal dysplasiasGüneş 2025 Read the full analysis | In 13 patients from 10 families with heterozygous TRPV4 variants, followed for a median of 6.5 years, SMDK and classic metatropic dysplasia showed short stature, kyphosis and activity-related pain emerging after about age 5 and progressing with age, whereas brachyolmia type 3 and the single CDSMA patient (p.Arg269His) showed scoliosis with preserved ambulation. Pelvic radiographs best distinguished SMDK (irregular proximal femoral metaphyses) from MD (femoral neck widening), and intrafamilial variability was observed. The series is small and descriptive and is analyzed here in its preprint form. | This study followed 13 people, mostly children, with bone and growth conditions caused by TRPV4 changes, for about six and a half years on average. In the two more severe types, children grew much shorter than average and developed a forward-curving back and pain on walking or climbing stairs, starting around age 5 and worsening with age. Hip X-rays helped tell these two types apart. One child had a nerve-related form called congenital distal SMA and was walking normally at about 9 years. | Doctors took X-rays of 13 people with TRPV4 bone conditions for several years. In some types, the back curved and walking got painful as children grew. This study is mostly about bones, not CMT2C. |
| #57TRPV4-pathy manifesting both skeletal dysplasia and peripheral neuropathy: a report of three patientsCho 2012 Read the full analysis | Three unrelated girls with TRPV4 skeletal dysplasia (spondylometaphyseal dysplasia Kozlowski type or spondyloepimetaphyseal dysplasia Maroteaux type) also had neurogenic involvement, ranging from motor or sensorimotor axonal neuropathy to denervation with normal nerve conduction, and carried E278K, P799R or de novo A217S. The authors find no consistent genotype-phenotype rule separating skeletal from neuropathic expression, and suggest skeletal features are highly penetrant while neuropathy shows reduced penetrance, based partly on an E278K-carrying mother without reported neuropathy. Evidence is clinical and genetic only, with no functional studies. | This paper describes three girls who each had a TRPV4 bone growth condition and also had damage to the nerves that control muscles. The changes in their TRPV4 genes were in different places, and the authors found no simple rule for which changes cause bone problems, nerve problems or both. One girl's mother had the same change and the bone condition, but was described as having no nerve problems. The authors suggest checking for bone changes in people with TRPV4 nerve disease, and the other way round. | The TRPV4 gene can cause bone problems or nerve problems, and these three girls had both. It is like one faulty part in a machine that can make it break in more than one way. Doctors still cannot predict which way it will go for each person. |
| #58TRPV4 mutations in children with congenital distal spinal muscular atrophyFiorillo 2012 Read the full analysis | Screening six patients with genetically unexplained congenital distal SMA identified new TRPV4 variants in two: P97R, located before the ankyrin repeats and the first distal SMA mutation found outside them, and R232C, previously reported with CMT2C; only these two had laryngeal or skeletal involvement. In HeLa cells, P97R reduced swelling-evoked calcium entry and reduced current to about 60% of normal, which the authors interpret as loss of function, in contrast to gain of function reported elsewhere for R232C. The authors find no consistent genotype-phenotype or genotype-function correlation and propose additional modifying factors. | Doctors tested the TRPV4 gene in six young patients who were born with leg weakness caused by damage to motor nerve cells, but had no genetic diagnosis. Two had a new TRPV4 change, and these were the only two who also had a hoarse voice or bone changes. In lab cells, one of the changes (P97R) made the channel work less than normal, while another lab had reported that the other change (R232C) makes it work more. The authors say the link between the type of change and the illness is not yet clear. | Two of six children born with weak legs had a change in their TRPV4 gene, and they were the ones with a croaky voice or bone problems. In a lab test, one child's TRPV4 door opened less than it should, not more. Scientists are still working out why different changes in the same door can cause similar illness. |
| #59The case of a highly trained TRPV4 related scapuloperoneal spinal muscular atrophy patient: a 5-year follow-upCrisafulli 2025 Read the full analysis | This single-patient longitudinal report describes TRPV4 (p.S94W) scapuloperoneal SMA in a man followed from about 21 to 26 years of age during supervised combined resistance and endurance training. MRC sum score (45, 52, 52), handgrip strength, VO2max (50.0, 51.9, 43.8 mL/min/kg) and phase angle were maintained or improved, with no reported adverse effects. Without a control or established natural history, the data support feasibility in this individual but cannot establish a disease-modifying effect. | This report follows one young man with a TRPV4-related condition that weakens the muscles around the shoulder blades and lower legs. He trained at a gym with professional guidance for about five years. His strength and sense of well-being stayed the same or got better, his fitness dipped only after a two-month break in training, and he reported no harmful effects. Because only one person was studied and there was no comparison group, it is not possible to say whether the exercise slowed the condition. | One young man with a TRPV4 condition went to the gym regularly for five years and stayed strong. That is good news for him, but from just one person we cannot tell whether exercise would help everyone. |
| #60Roles for TRPV4 in disease: A discussion of possible mechanismsHernández-Vega 2024 Read the full analysis | This narrative review summarizes TRPV4 structure, regulation and tissue expression and catalogs reported skeletal, neuromuscular and putative PKD-associated variants, most characterized as gain of function. For neuropathy it cites evidence that mutant channels raise intracellular Ca2+, disrupt axonal mitochondrial transport and RhoA binding at the ankyrin repeat domain, and, in R232C and R269C knock-in mice, impair blood-spinal cord barrier integrity, with antagonist rescue of lethality in R269C mice. The authors note that Ca2+ excess does not fully explain the phenotypes and that most data come from heterologous expression systems. | This article reviews earlier research rather than reporting new experiments. TRPV4 is a channel, a tiny gate in the cell surface that lets calcium in, and most disease-causing changes seem to make this gate too active. In cells grown in the lab and in mice, this was linked to damaged nerve fibers, and in one mouse study a TRPV4-blocking drug prevented early death. The authors say extra calcium does not explain everything and that results from lab cells may not match the whole human body. | TRPV4 is like a door that lets calcium into cells. Many TRPV4 changes seem to leave the door open too much, which harmed nerve cells in lab dishes and in mice. Scientists still do not know exactly how this works in people. |
| #61Axonal neuropathy-associated TRPV4 regulates neurotrophic factor-derived axonal growthJang 2012 Read the full analysis | In rat PC12 cells and neonatal rat DRG neurons, TRPV4 overexpression or agonists (4α-PDD, 5,6-EET, arachidonic acid, GSK1016790A) enhanced NGF-driven neuritogenesis, whereas siRNA knockdown or antagonists (HC-067047, ruthenium red) reduced it. NGF and cAMP upregulated PLA2 and TRPV4 through a MEK-dependent pathway, and TRPV4 activation increased F-actin and cell adhesion. No neuropathy-causing TRPV4 variants were examined, so the relevance to CMT2C pathogenesis remains inferential. | In mice, TRPV4 is found in the nerve cells that control movement and feeling. In rat cells grown in dishes, turning TRPV4 up or switching it on with chemicals made nerve fibers grow longer, and turning it down made them shorter. The study did not test the gene changes that cause CMT2C, so it shows what TRPV4 normally does rather than what goes wrong in the disease. | TRPV4 is like a door that lets calcium into nerve cells. In rat cells in a dish, opening the door more helped the nerve's long arms grow, and closing it slowed them down. But the scientists did not test the faulty door that causes CMT2C. |
| #62De novo TRPV4 Leu619Pro variant causes a new channelopathy characterised by giant cell lesions of the jaws and skull, skeletal abnormalities and polyneuropathyRagamin 2022 Read the full analysis | Two unrelated women carried de novo TRPV4 variants producing p.Leu619Pro in the S5 transmembrane helix and shared a multisystem phenotype: recurrent aggressive giant cell-rich lesions of the jaws and skull, skeletal anomalies, vocal cord paresis, hearing loss and polyneuropathy (motor axonal on nerve conduction in one). A low variant allele fraction in the milder case (21.6% in blood) was interpreted as postzygotic mosaicism. Gain of function was inferred from structural modeling and earlier work rather than tested, so the genotype-phenotype link rests on two cases. | Two young women in different countries had the same new change in the TRPV4 gene, which neither set of parents had. Both had nerve damage, weak vocal cords, hearing loss and skeletal problems, plus bone growths in the jaw and skull that kept coming back after surgery. One woman may carry the change in only some of her cells, which could explain why she was less severely affected. The researchers predicted from a computer model that the change makes the channel leak, but did not test this in the lab. | TRPV4 is like a door that lets calcium into cells. Two women had a change near the opening of the door that might make it leak, and they had problems with their nerves, hearing and face bones. Doctors know of only two people with this change, so there is still a lot to learn. |
| #63Homozygous TRPV4 mutation causes congenital distal spinal muscular atrophy and arthrogryposisVelilla 2019 Read the full analysis | Exome sequencing in a boy with congenital distal SMA with arthrogryposis, bilateral vocal cord immobility and normal sensory responses identified homozygous TRPV4 p.S94L in the N-terminal disordered region, with both parents heterozygous and an unaffected sister homozygous for the reference allele. In HEK293 cells S94L increased cytotoxicity and lowered protein levels, both reversed by the TRPV4 antagonist HC-067047, which the authors interpret as gain of function, although channel activity was not measured directly. They propose a recessive form of the disease and reduced penetrance in heterozygotes, but the parents' status is not described as based on examination. | Most TRPV4 conditions happen when one copy of the gene is changed. This boy had the same change in both copies, one from each parent. He was born with stiff, bent joints, could not move his vocal cords and had weak legs. In lab cells the changed channel harmed the cells, and a TRPV4 blocker stopped this. The parents, who each carry one copy, were described as healthy, but the paper does not say they were examined. | Everyone has two copies of the TRPV4 instructions. This boy got the same small mistake from both his mom and his dad, and he was born with stiff joints and weak legs. In a dish, the faulty calcium door harmed cells, and a door-blocking chemical stopped it. His parents each have one faulty copy and seem well, but the paper does not say anyone checked their nerves. |
| #64Homozygous TRPV4 Mutation Broadens the Phenotypic Spectrum of Congenital Spinal Muscular Atrophy and Arthrogryposis: A Case ReportLugo 2023 Read the full analysis | A boy with homozygous TRPV4 c.281C>T (p.S94L) presented with congenital bilateral knee arthrogryposis, talipes equinovarus and ambulatory delay, with normal sensory nerve conduction, reduced peroneal CMAP amplitude and neurogenic EMG changes, and without skeletal dysplasia or vocal fold paralysis. The authors classify this as congenital spinal muscular atrophy and arthrogryposis and, noting a previous Puerto Rican case with the same variant, raise a possible founder effect. Heterozygous parents were reported as clinically unaffected, but their assessment is not described. | This is a report on one young boy. He inherited the same TRPV4 change from both parents, so he has two changed copies. He was born with stiff knees and clubfeet and at two years could not stand or walk on his own, but his arms, speech and hearing were normal. Nerve tests suggested the problem lay in the nerve cells that control muscles, not in the nerves for feeling. His parents each carry one copy and were said to be healthy, but the report does not say how they were checked. | This is the story of one little boy who got the same TRPV4 change from his mom and his dad. He was born with stiff knees and turned-in feet and finds standing and walking hard, but his arms work well. His parents each have one copy and seem well, but we do not know how carefully they were checked. |
| #65Case Report: TRPV4 gene mutation causing neuronopathy, distal hereditary motor, type VIIIWang 2024 Read the full analysis | A 7-year-old boy with prenatally detected bilateral clubfoot, distal lower-limb weakness and atrophy, and inability to walk independently carried a heterozygous TRPV4 c.805C>T (p.Arg269Cys) variant inherited from his father. The father had unremarkable muscle MRI and electrophysiology and was considered a non-manifesting carrier or very mildly affected, consistent with incomplete penetrance or variable expressivity. The authors diagnosed distal hereditary motor neuronopathy type VIII, although no electrophysiology or sensory testing of the proband is reported. | A 7-year-old boy was born with both feet turned inward (clubfoot) and has weak, thin leg muscles, so he cannot walk on his own. Genetic testing found a change in the TRPV4 gene that he inherited from his father. His father seems healthy, and his muscle scans and electrical tests looked normal, so he may carry the change without showing it, or have signs too mild to notice. The doctors called the boy's illness a motor-only nerve condition, but the paper does not report the nerve tests that would confirm this. | A boy got a change in a gene called TRPV4 from his dad. TRPV4 is like a door that lets calcium into cells. The boy's legs are weak and he cannot walk alone, but his dad seems fine, so the same gene change can affect people in one family very differently. |
| #66Muscle MRI in TRPV4-related congenital distal SMAAstrea 2012 Read the full analysis | Lower-limb muscle MRI in two children with TRPV4-related congenital distal SMA and one adult with CMT2C showed predominant fatty replacement of the anterior calf compartment (tibialis and peroneal groups) with relative sparing of medial gastrocnemius, and more extensive thigh involvement in congenital distal SMA. The authors propose a continuum of muscle involvement across TRPV4 phenotypes, distinct from a single DYNC1H1 comparison case. With three patients and no described scoring or blinding, this is a preliminary observation. | Doctors scanned the leg muscles of three people with TRPV4 changes: two children with a form of spinal muscular atrophy present from birth and one man with CMT2C. In all three, the muscles at the front of the lower leg had been replaced by fat the most, while one calf muscle was spared. The children's thigh muscles were more affected than the man's. This hints that the conditions form one spectrum, but three people is too few to be sure. | Doctors took special pictures of the leg muscles of three people with TRPV4 changes. The same muscles at the front of the lower leg looked most worn in all three. It is a bit like the same spot wearing out first on three pairs of shoes. But three people are too few to know if this is always true. |
| #67The Broad Clinical Spectrum of Metatropic Dysplasia: A Case Series and Literature ReviewRobles-Espinoza 2025 Read the full analysis | Three unrelated patients with metatropic dysplasia carried de novo or presumed de novo TRPV4 variants in the carboxyl-terminal cytoplasmic domain (p.Asn796del; p.Pro799Leu in two), with marked variability in extra-skeletal features (seizures, developmental delay, spinal dysraphism, fractures) even for the same variant. Combining these with published cases (52 patients, 44 families), the authors propose a single TRPV4 severity continuum spanning skeletal dysplasia and neuropathy, but none of the three had a reported peripheral nerve evaluation, so the neuropathy side of this model is not tested here. | The doctors describe three Mexican children with metatropic dysplasia, a rare condition affecting bone growth that is caused by TRPV4 changes. Two of them had exactly the same gene change, yet one did well and the other had seizures, slow development and broken bones. The authors argue that TRPV4 bone conditions and TRPV4 nerve conditions such as CMT2C are one family of diseases with different levels of severity. However, the children's nerves were not tested, so this paper does not show nerve damage in them. | TRPV4 is like a door that lets calcium into cells, and these three children have changes in it that affect how their bones grow. Two children had exactly the same change but very different health. The doctors think bone and nerve TRPV4 illnesses belong to one big family, but they did not test these children's nerves. |
| #68Compound heterozygous TRPV4 mutations in two siblings with a complex phenotype including severe intellectual disability and neuropathyThibodeau 2017 Read the full analysis | Two siblings who were compound heterozygous for the TRPV4 variants Asn833Ser and Glu840Lys, both located away from the ankyrin repeat domain, had a severe multisystem phenotype including axonal sensorimotor neuropathy, sensorineural hearing loss, retinal disease, short stature and profound intellectual disability, while heterozygous relatives were reported as well. In Chinese hamster ovary cells each variant trafficked normally but produced about a third of wild-type current, suggesting partial loss of function. The authors propose biallelic reduced channel function as a new TRPV4 disease mechanism, but the evidence comes from one family and the variants were never co-expressed. | Two children in one family each inherited two different changes in the TRPV4 gene, one from their father's side and one from their mother. They had a severe condition affecting their nerves, hearing, eyesight, growth and learning, while relatives with only one of the changes were described as well. In lab-grown hamster cells, each changed channel let through only about a third of the normal electrical current. The authors suggest that having too little working channel, inherited from both parents, is a new way TRPV4 can cause disease. | Think of TRPV4 as a door that lets calcium into cells. These two children got a slightly broken door from each parent, and in lab tests each of these doors only opened about a third as much as normal. The children were very unwell, but this is just one family, so scientists need to see more families to be sure. |
| #69TRPV4-pathy, a novel channelopathy affecting diverse systemsDai 2010 Read the full analysis | This 2010 review groups the autosomal dominant TRPV4 skeletal dysplasias (29 mutations) and the neuromuscular disorders (congenital distal SMA, scapuloperoneal SMA and HMSN IIC; four arginine substitutions at three ankyrin repeat positions) into a single channelopathy, 'TRPV4-pathy'. The authors argue that ankyrin repeat location and arginine substitution are not specific to neuropathy, that published functional data conflict, and that a simple gain-of-function or loss-of-function model cannot explain the phenotypic divergence. They propose interacting proteins or aberrant endoplasmic reticulum signaling as alternatives, without presenting new data. | TRPV4 is a gene that makes a channel, a kind of gate that lets calcium and similar particles into cells. Changes in this gene were first linked to conditions affecting bone growth, and then to nerve and muscle conditions including CMT2C. The authors grouped all of these under the name 'TRPV4-pathy'. They argued that the early explanations of how the faulty channel causes disease were probably too simple, but they offered ideas rather than new evidence. | One gene, TRPV4, makes a door that lets calcium into cells. Changes in this door can cause bone problems in some people and nerve problems, like CMT2C, in others. The scientists who wrote this said nobody yet knew why, and shared their best guesses. |
| #70TRPV4-mediated channelopathiesVerma 2010 Read the full analysis | This 2010 narrative review catalogs 35 naturally occurring and 56 engineered TRPV4 mutations and highlights conflicting gain-of-function and loss-of-function data for ankyrin repeat domain neuropathy mutations, depending on the cell line (HEK versus HeLa). The authors hypothesize that these mutations alter oligomerization, trafficking, ubiquitination-dependent surface expression or binding of an unidentified inhibitory complex, rather than conductance alone. These models are explicitly hypothetical and untested. | This article reviews research on the TRPV4 channel up to 2010. At that time, lab studies disagreed about whether the neuropathy mutations made the channel more active or less active, and the answer seemed to depend on the type of cell used. The authors suggest the mutations might change how the channel is built, moved to the cell surface or held shut by other proteins, but these were ideas to be tested, not proven results. | TRPV4 is like a door that lets calcium into a cell. In 2010, scientists were not sure whether faulty versions of the door were stuck open or stuck shut. These authors guessed that helper proteins that normally hold the door closed might be part of the problem. |
| #71Natural history of TRPV4-Related disorders: From skeletal dysplasia to neuromuscular phenotypeÜrel-Demir 2021 Read the full analysis | This single-center series reports 11 patients from six families with TRPV4-related disorders, framed as a spectrum spanning skeletal dysplasias and neuromuscular phenotypes (congenital distal SMA, scapuloperoneal SMA and CMT2C) with considerable overlap within and between groups. The abstract gives no genotype, phenotype or longitudinal data, so its natural history findings cannot be assessed. | Doctors in Turkey describe 11 people from six families with conditions caused by changes in the TRPV4 gene. These conditions range from problems with bone growth to nerve and muscle problems such as CMT2C, and many people have features of more than one. The abstract does not describe what was found in each patient. | Changes in the TRPV4 gene can affect bones, nerves and muscles, and often more than one. This study looked at 11 people with these changes, but the summary does not say what happened to them. |
| #72TRPV4 related scapuloperoneal spinal muscular atrophy: Report of an Italian family and review of the literatureBiasini 2016 Read the full analysis | In the first Italian SPSMA family, the TRPV4 R269H variant showed variable expressivity: mild muscular involvement in the father and congenital skeletal dysplasia with a progressive course in the son. The authors interpret this as supporting greater severity in successive generations and recommend considering SPSMA in autosomal dominant neurogenic scapuloperoneal syndromes, particularly with skeletal deformities. A single parent-child pair cannot establish anticipation, and methods cannot be assessed from the abstract. | Doctors describe an Italian father and son with the same TRPV4 change, R269H, which caused weakness around the shoulder blades and lower legs. The father was only mildly affected, while the son had bone problems from birth and got worse over time. The authors think the illness can be more severe in later generations, but this is based on one father and son. | A dad and his son had the same TRPV4 change. The dad was only a little weak, but the son had more problems from when he was born. |
| #73Fetal akinesia in metatropic dysplasia: The combined phenotype of chondrodysplasia and neuropathy?Unger 2011 Read the full analysis | Four cases of severe metatropic dysplasia with de novo heterozygous TRPV4 mutations (G78W, T740I, K276E) presented with fetal akinesia, detected on second-trimester ultrasound or as arthrogryposis with absent limb movements at birth. The authors propose that certain TRPV4 mutations cause both chondrodysplasia and peripheral neuropathy, a severe overlap phenotype. The abstract does not report neurophysiological or pathological confirmation of neuropathy. | Doctors describe four babies with a severe TRPV4 bone growth condition who did not move in the womb or at birth. All had new changes in the TRPV4 gene that were not inherited. The authors think these changes may affect the nerves as well as the bones, but the abstract does not describe nerve tests. | Four babies with a TRPV4 change had bones that grew differently, and they hardly moved before birth. Doctors think their nerves might have been affected too, but they did not show this for sure. |
| #74Novel TRPV4 mutation in a large Chinese family with congenital distal spinal muscular atrophy, skeletal dysplasia and scaly skinLiu 2020 Read the full analysis | In a large Chinese pedigree, a novel heterozygous TRPV4 variant, c.2355G > T (p.Trp785Cys), identified by whole-exome sequencing, co-segregated with congenital distal SMA, skeletal abnormalities including femoral head osteonecrosis, and scaly skin in five affected members. The authors interpret this as an expansion of the TRPV4 phenotypic spectrum. Phenotyping of unaffected relatives and functional evidence cannot be assessed from the abstract. | Doctors studied a large family in China in which five people had scaly skin, bone problems in the hip and elsewhere, and leg weakness from birth caused by damaged motor nerve cells. They found a new change in the TRPV4 gene in these relatives. The change appeared to travel with the illness through the family. | In one big family, five people had weak legs from birth, bone problems and scaly skin, and they all had the same new change in their TRPV4 gene. |
| #75TRPV4-associated skeletal dysplasiasNishimura 2012 Read the full analysis | This review describes TRPV4 skeletal dysplasias as a continuous spectrum from lethal metatropic dysplasia through spondylometaphyseal dysplasia Kozlowski type to autosomal dominant brachyolmia, with rarer variant phenotypes and a small number of combined skeletal and neuropathic cases. Among more than 50 reported mutations, it notes hot spots at P799 and R594. Most mutations tested show gain of function in vitro, though mechanisms and genotype-phenotype correlations remain unclear. Its handling of the neuropathy overlap cannot be judged from the abstract. | This article reviews the bone growth conditions caused by changes in the TRPV4 gene, which range from very severe to mild. A small number of people have both a bone condition and nerve damage from the same TRPV4 change. In lab tests most of these changes make the channel more active, but how that leads to bone or nerve problems was not yet understood. | TRPV4 is like a door that lets calcium into cells. Many TRPV4 changes cause problems with how bones grow, and a few people also get nerve problems. In lab tests most of these changes left the door stuck too far open, but scientists did not yet know how that causes illness. |
| #76Spondyloepimetaphyseal dysplasia-Maroteaux type due to dominant TRPV4 mutation: expanding the phenotype with a case reportUzman 2023 Read the full analysis | A boy with spondyloepimetaphyseal dysplasia Maroteaux type and a dominant TRPV4 mutation showed reduced lumbar interpedicular distance, congenital contractures and an arachnoid cyst, which the authors present as previously unreported features. Whether these are TRPV4-related or coincidental cannot be determined from a single case, and neurological assessment is not described in the abstract. | Doctors describe a boy with a bone growth condition caused by a change in the TRPV4 gene. He also had some features not reported before in this condition, including joints that were stiff from birth and a small fluid-filled sac near the brain or spine. With only one patient, it is not clear whether these features are caused by the TRPV4 change. | A boy with a TRPV4 change had bones that grew differently and joints that were stiff from birth. Doctors wrote about him so others can spot the condition. |
| #77TRPV4 acts as a mitochondrial Ca2+-importer and regulates mitochondrial temperature and metabolismKanta Acharya 2022 Read the full analysis | In various cell lines, TRPV4 localized to a subpopulation of mitochondria, and altered TRPV4 expression or function induced mitochondrial abnormalities, with TRPV4 implicated in regulating mitochondrial number, Ca2+ levels and temperature. Several naturally occurring TRPV4 mutations altered mitochondrial morphology and distribution, leading the authors to propose that TRPV4 channelopathies might be considered mitochondrial diseases. The cell systems and mutations studied cannot be assessed from the abstract. | Mitochondria are tiny parts inside cells that make energy. This lab study found that the TRPV4 channel sits on some mitochondria, and that when TRPV4 was abnormal, the mitochondria changed in number, calcium level, temperature and shape. The authors suggest TRPV4 conditions might be partly diseases of the mitochondria, but the findings come only from cells grown in a dish. | Mitochondria are like tiny batteries inside our cells. Scientists found the TRPV4 door on some of these batteries, and when the door was faulty the batteries did not look or work normally in lab cells. |
| #78The mutational spectrum in a cohort of Charcot-Marie-Tooth disease type 2 among the Han Chinese in TaiwanLin 2011 Read the full analysis | Direct (dideoxy) sequencing of CMT2-associated genes in 36 unrelated Han Chinese CMT2 probands identified pathogenic variants in 14 (38.9%), mostly in NEFL (16.7%) and MFN2 (13.9%), with six novel variants supported by conservation, absence from controls and limited segregation. No TRPV4 variants were detected, and 61.1% remained genetically unexplained. The cohort is small and from a single center, so the absence of TRPV4 variants gives only an imprecise estimate of CMT2C frequency in this population. | In 36 unrelated people from Taiwan, the researchers checked the genes known at the time to cause the axonal form of CMT (CMT2). They found the cause in 14 people, most often in two genes called NEFL and MFN2. Nobody had a change in TRPV4, the CMT2C gene, and most people still had no genetic answer. | Doctors looked for spelling mistakes in a set of genes in 36 people with a nerve illness called CMT2. They found mistakes in some genes, but none in TRPV4, the calcium door gene linked to CMT2C. For many people the cause is still a mystery. |
| #79Phenotype Presentation and Molecular Diagnostic Yield in Non-5q Spinal Muscular AtrophyFernández-Eulate 2023 Read the full analysis | In a retrospective series of 71 adults with non-5q SMA from French and London reference centers, a molecular diagnosis was reached in 32 (45.1%), most often in BICD2, DYNC1H1 and TRPV4; neuropathy gene panels alone yielded 19/59 (32.2%). Yield was highest in scapuloperoneal presentations and was independently predicted by earlier onset and family history or consanguinity. The 4 TRPV4 patients mostly had scapuloperoneal SMA with adult-onset weakness, areflexia and frequent vocal cord paralysis and respiratory involvement, a subgroup too small for firm conclusions. | This study looked back at the records of 71 adults who had weakness caused by damage to the nerves that move muscles but did not have the usual gene change behind spinal muscular atrophy. Doctors found the genetic cause in fewer than half. TRPV4 was one of the three most common causes, found in 4 people from 3 families. Those 4 mostly had weak shoulder-blade and lower leg muscles starting in adult life, and 3 had vocal cord weakness. | Doctors looked at 71 adults whose muscles were weak because of nerve problems and searched their genes for the cause. They found it in a bit less than half of them. TRPV4, the gene for a calcium door in cells, was the cause in only 4 people, so we cannot learn much about TRPV4 from this study alone. |
| #80Charcot-Marie-Tooth disease: New insights from skin biopsyManganelli 2015 Read the full analysis | Fingertip skin biopsies from 31 genetically defined CMT patients, including 3 with CMT2C, showed reduced Meissner corpuscle and intrapapillary myelinated ending densities in every genotype compared with 45 controls, with a tendency to greater loss in axonal forms, especially CMT2C. Dermal myelinated fibers in all genotypes, including TRPV4, had shortened internodes and widened nodal gaps, most marked in CMT1A, suggesting shared developmental and axon-glial abnormalities. CMT2C-specific observations rest on 3 patients and descriptive comparisons. | Researchers took a tiny piece of fingertip skin from people with different types of CMT, including three people with CMT2C, and from healthy people. Everyone with CMT had fewer touch sensors and nerve endings in the skin than healthy people, and the loss tended to be greater in the CMT2C group. The insulated sections of nerve fibers were shorter, and the gaps between them wider, in all types of CMT. With only three people with CMT2C, the CMT2C results are a hint rather than a firm finding. | Doctors looked at tiny bits of fingertip skin under a microscope. People with CMT, including three with CMT2C, had fewer of the little touch sensors than healthy people. Three people is a very small group, so this is only a first clue. |
| #81Improved inherited peripheral neuropathy genetic diagnosis by whole-exome sequencingDrew 2015 Read the full analysis | Whole-exome sequencing of 110 index patients with genetically unresolved inherited peripheral neuropathy identified previously reported pathogenic mutations in 9 families (8%, in MFN2, GJB1, BSCL2 and SETX) and 12 novel candidate variants (11%) whose pathogenicity remains unproven. The only TRPV4 finding, p.E183D in a patient with axonal sensorimotor neuropathy and retinal degeneration, could not be tested for segregation, was predicted tolerated by SIFT and Polyphen-2, and was considered a probable rare polymorphism. Several internal count discrepancies reduce confidence in exact figures. | The researchers read all the genes of 110 people with inherited nerve disease whose cause had not been found by standard tests. They found a known cause in 9 families and possible new causes in 12 more, but those 12 could not be proven. One person had a rare change in TRPV4, but computer checks suggested it was probably harmless and no relatives could be tested. | Scientists read the whole instruction book of 110 people with nerve problems to look for typing mistakes. They found the cause for some families, and one person had a small change on the TRPV4 page that looked like a harmless typo, though they could not be completely sure. |
| #82Development and validation of the Charcot-Marie-Tooth Disease Infant ScaleMandarakas 2018 Read the full analysis | The authors developed the CMT Infant Scale (CMTInfS), a 15-item, Rasch-built functional outcome measure for children aged 0 to 4 years, from a 31-item pool tested in 128 children (26 with confirmed inherited neuropathy, 7 at risk, 95 controls). Scores are expressed as z-scores against age- and gender-matched normative values. The scale showed good Rasch model fit, high intra- and inter-rater reliability, discrimination between affected children and controls, and correlation with the CMTPedS (r = 0.76). Responsiveness was examined in only four children with CMT1A, and only one child with CMT2C was included. | Researchers need a reliable way to measure how much CMT affects very young children before trials can include them. This team built a play-based test that takes about 20 minutes and has 15 tasks, such as sitting, rolling and tearing paper. Different testers gave very similar scores, and children with CMT scored worse than healthy children. Only one child with CMT2C took part, and change over time was checked in just four children with another type of CMT. | Scientists made a set of play tasks, like sitting up and tearing paper, to measure how CMT affects babies and toddlers. The tasks are a bit like a ruler for movement skills. They worked well in tests, but only one child with CMT2C was included. |
| #83Expanding the Genotype and Phenotype Diversity in a Chinese Cohort With TRPV4-Related DysplasiaDong 2026 Read the full analysis | In a retrospective single-center series of 10 Chinese patients with TRPV4-related skeletal dysplasia (6 SMDK, 4 MD), scoliosis (9/10), platyspondyly, metaphyseal changes and joint contractures were common, and two MD patients had neurological deficits attributed to spinal cord compression. Variants associated elsewhere with other phenotypes (P799L, R616Q and the neuropathy-associated R232C) occurred in SMDK, and a novel p.L543R variant was classified as a VUS, consistent with the absence of a clear genotype-phenotype correlation. No nerve conduction studies are reported, so peripheral nerve involvement was not objectively assessed. | Doctors looked back at the records of 10 Chinese patients whose TRPV4 change caused problems with bone growth. Most had a curved spine and stiff joints, and two with the more severe type had nerve problems because the spine pressed on the spinal cord. The same TRPV4 change could go with different conditions: R232C, a change also reported in nerve disease, was found in a patient with a bone condition, though nerve tests were not reported. | Changes in TRPV4 can affect bones as well as nerves. In 10 patients with bone problems, the same gene change did not always cause the same problem, a bit like the same recipe turning out differently in different kitchens. |
| #84The distal hereditary motor neuropathiesRossor 2012 Read the full analysis | This narrative review covers the distal hereditary motor neuropathies, a genetically heterogeneous group overlapping with CMT2, in which more than 80% of patients lacked a genetic diagnosis at the time. TRPV4 is listed among the causes of dHMN type VII (vocal cord paralysis) and is also linked to scapuloperoneal SMA and CMT2C, with marked intrafamilial variability. On the in vitro evidence then available, the authors considered a toxic gain of function the most likely mechanism, while urging caution about antagonists given the phenotypes of TRPV4 knockout mice. | This 2012 review describes a group of inherited nerve conditions that mainly weaken the muscles of the hands and feet, called distal hereditary motor neuropathies. They overlap with the axonal type of Charcot-Marie-Tooth disease. The review says TRPV4 changes are one cause, often with weak vocal cords, and that symptoms can differ a lot between relatives. At the time, scientists thought the faulty channel probably let in too much calcium, but the evidence was mixed. | Some families have nerve problems that mostly make the hands and feet weak. TRPV4, a door that lets calcium into cells, is one of many genes that can cause this. Back then, scientists thought the door might be letting in too much calcium, but they were not sure yet. |
| #85TRPV4: A trigger of pathological RhoA activation in neurological diseaseBagnell 2022 Read the full analysis | This hypothesis review proposes that TRPV4 and the small GTPase RhoA form a mechanosensitive signaling complex: inactive TRPV4 sequesters GDP-bound RhoA, while TRPV4-mediated calcium influx releases and activates RhoA, driving ROCK-dependent actin remodeling. Drawing mainly on rodent models of stroke, traumatic brain injury and spinal cord injury, the authors argue that this axis impairs axon regeneration and blood-brain barrier integrity, and that TRPV4 antagonists could limit pathological RhoA activation. Evidence relating to inherited TRPV4 neuropathy is limited to cell and Drosophila work, and neuronal TRPV4 expression is described as debatable. | TRPV4 is a channel that senses things like pressure and swelling around a cell. RhoA is a switch protein that makes the cell's internal scaffolding tighten and pull back. The authors suggest that when TRPV4 is switched on too much, for example after a stroke or spinal injury, it turns on RhoA, which may stop nerves from regrowing and make blood vessels in the brain leaky. They suggest TRPV4-blocking drugs as a possible treatment, but this idea rests mostly on animal studies and has not been tested in people with nerve disease. | TRPV4 is like a door in a cell that also works a switch called RhoA. When the door opens too much, the switch can make the cell scrunch up. The authors think blocking the door might help after nerve injuries, but so far this idea has mostly been tested in animals. |
| #86TRPV4 interacts with mitochondrial proteins and acts as a mitochondrial structure-function regulatorKumar 2018 Read the full analysis | In cell lines, primary endothelial cells, isolated brain mitochondria and sperm, wild-type TRPV4 localized to a subset of mitochondria, and pharmacological activation with 4αPDD altered mitochondrial morphology, lowered membrane potential, increased mitochondrial calcium and reduced complex II and IV activity, whereas RN1734 had opposite or no effects. A recombinant C-terminal fragment bound Hsp60, Mfn1 and Mfn2 in pull-down assays. No neuropathy-associated variants were studied, so any role in CMT2C pathogenesis remains a hypothesis, and the work is an unreviewed preprint. | Mitochondria are tiny parts inside cells that make energy. This study suggests that TRPV4 is found on some mitochondria, and that switching TRPV4 on with a drug changed their shape and how well they worked, in cells grown in a dish. The authors suggest this might connect TRPV4 to nerve diseases like CMT, but they did not test any of the gene changes that cause CMT2C, and the paper has not been checked by independent reviewers. | Cells have tiny power stations called mitochondria. These scientists think the TRPV4 calcium door might also sit on some of the power stations and change how they work. It is an early idea from lab tests, and they did not look at the CMT2C version of the door. |
| #87Hearing loss in inherited peripheral neuropathies: Molecular diagnosis by NGS in a French seriesLerat 2019 Read the full analysis | In a retrospective French series of 3,412 patients with inherited peripheral neuropathy, record-based ascertainment identified hearing loss in 44 (1.30%), of whom 27 had usable data; panel NGS gave a molecular diagnosis in 16 of 27 (59.26%). Hearing loss was cochlear and/or retrocochlear, with auditory neuropathy in five, including one TRPV4 p.(Arg232Cys) carrier with familial axonal sensorimotor neuropathy and bilateral vocal cord paresis. Only one of five TRPV4 carriers in the series had documented hearing loss, but ascertainment bias prevents any estimate of its frequency. | Researchers searched the records of 3,412 French people with inherited nerve disease and found hearing loss noted in only 44. Gene tests found a cause in 16 of the 27 people with enough information. One man had a TRPV4 change; his hearing loss came from the hearing nerve rather than the inner ear, and he also had weak vocal cords. Because hearing loss was found from records rather than by testing everyone's hearing, the study cannot say how often hearing loss happens in TRPV4 disease. | Doctors looked at many people with nerve illnesses to see who also had trouble hearing. One man with a TRPV4 gene change had a problem in the nerve that carries sound signals, like a phone line with a bad connection, and he also had weak vocal cords. The doctors mostly used old records instead of testing everyone's hearing, so we do not know how common this is. |
| #88Disruption of genes associated with Charcot-Marie-Tooth type 2 lead to common behavioural, cellular and molecular defects in Caenorhabditis elegansSoh 2020 Read the full analysis | In C. elegans, loss-of-function alleles of nine CMT2-associated orthologs or paralogs caused locomotor deficits in most strains, myofilament disorganization, and, for lin-41, dyn-1, unc-116 and fzo-1, reduced spontaneous postsynaptic current frequency at the neuromuscular junction. The osm-9 (TRPV4 counterpart) mutant showed adult-onset swimming deficits, reduced crawling, moderate muscle structural changes and altered levamisole responses, but normal DA/DB motor neuron morphology, population motility and neuromuscular junction current frequency. As null models of a gene whose CMT2C form is autosomal dominant, these data inform normal gene function rather than CMT2C pathogenesis. | Researchers used tiny worms to study nine genes linked to the axonal type of Charcot-Marie-Tooth disease. For each gene, they used worms in which the worm's own version of that gene did not work. Worms lacking their TRPV4-like gene, called osm-9, swam and crawled less well as adults and had some muscle changes, but their motor nerves and nerve-to-muscle signals looked normal. People with CMT2C carry a changed TRPV4 gene rather than a missing one, so these worms are only a distant model. | Scientists studied tiny worms that were missing genes linked to CMT. Worms missing their version of the TRPV4 gene moved a bit worse when they were older. But worms are very different from people, and these worms were missing the gene instead of having a changed one, so this does not tell us much about CMT2C yet. |
| #89Lysosomal Regulation of Inter-mitochondrial Contact Fate and Motility in Charcot-Marie-Tooth Type 2Wong 2019 Read the full analysis | Using live super-resolution and confocal imaging, mainly in HeLa cells, the authors show that mitochondria frequently form inter-mitochondrial contacts that restrict motility, with untethering promoted by mitochondria-lysosome contacts via RAB7 GTP hydrolysis and by Drp1, and tethering promoted by Mfn1/2. Overexpressed CMT2A (Mfn2 T105M), CMT2B (RAB7 V162M) and CMT2C (TRPV4 R269H) mutants each prolonged inter-mitochondrial contacts and reduced mitochondrial motility. For TRPV4 this rests on a single experiment in cultured cells, with no mechanism tested. | Mitochondria are the cell's power stations. This study found that they often stick to each other for a short time, and while stuck they move around less. Lysosomes, the cell's recycling centers, help them come apart. When the researchers added a CMT2C-linked TRPV4 change to cells grown in the lab, the power stations stayed stuck together longer and moved less. This was one small experiment in lab cells, not in nerves. | Inside cells, little power stations called mitochondria bump into each other and stick for a while. When cells had a faulty TRPV4, the power stations stayed stuck longer and moved less, a bit like cars in a traffic jam. This was only tested in cells in a dish, not in real nerves. |
| #90A New Mutation in FIG4 Causes a Severe Form of CMT4J Involving TRPV4 in the Pathogenic CascadeGentil 2017 Read the full analysis | A compound heterozygous FIG4 genotype (p.I41T with a novel IVS17-10 T>G variant) was associated with severe CMT4J, markedly reduced FIG4 protein, vacuolation and dispersed endolysosomal compartments in patient fibroblasts. TRPV4 protein was increased and retained at the plasma membrane with slower FRAP recovery, and the TRPV4 antagonist GSK2193874 partially delayed death of Fig4-knockout murine motor neurons without correcting vesicular defects. TRPV4 channel activity was not measured, so a TRPV4 gain of function in CMT4J remains inferred. | This paper describes a man with a severe form of CMT caused by a different gene, FIG4. In his skin cells the FIG4 protein was almost missing, the cells filled with bubbles, and more TRPV4 channel than normal sat on the cell surface. In mouse nerve cells grown in a dish, a drug that blocks TRPV4 helped cells without Fig4 live longer, but the researchers never measured whether the extra TRPV4 was actually letting in more calcium. | A different gene, FIG4, helps cells move and recycle their parts. When it was broken, more TRPV4 doors piled up on the cell surface. Blocking those doors helped mouse nerve cells in a dish live a bit longer, but nobody checked whether the doors were really letting in too much. |
| #91Protein informatics combined with multiple data sources enriches the clinical characterization of novel TRPV4 variant causing an intermediate skeletal dysplasiaHines 2019 Read the full analysis | A heterozygous TRPV4 c.2401A>G (p.K801E) variant, found by exome sequencing in a 47-year-old woman with features between spondyloepiphyseal dysplasia Maroteaux type and spondylometaphyseal dysplasia Kozlowski type, was also present in her daughter. Monte Carlo-refined structural models predicted reduced subunit stability and weaker inter-subunit interaction near the pore. The authors call the variant pathogenic and 'plausibly likely' gain of function, but no functional assay was performed, segregation rests on the proband and her affected daughter, and the discussion states that gain versus loss of function cannot be determined. | This paper describes a woman with an inherited bone-growth condition, her daughter and her late father. Genetic testing found a new change in the TRPV4 gene in the woman and her daughter. The researchers used computer models of the TRPV4 protein and predicted that the change makes the channel less stable. They describe the change as disease-causing, but they did not test how the channel actually works in cells, and they say they cannot tell whether it makes the channel more or less active. | A mom and her daughter share a new spelling change in the TRPV4 gene, and both have bone problems. A computer drawing of the TRPV4 'door' suggests the change makes it wobblier, but nobody tested the real door, so we cannot be sure what it does. |
| #92Long-term follow-up of metatropic dysplasia caused by novel mutations in the TRPV4 gene: Case report and literature reviewLiu 2025 Read the full analysis | A de novo heterozygous TRPV4 missense variant in exon 11 (c.1811T > A, p.I604N) was identified in a girl with radiologically typical metatropic dysplasia followed from 3 months to 7 years, with progressive kyphoscoliosis treated by vertebral column resection and fusion at age 5. The authors attribute her severe lower limb weakness to a combined skeletal and neuromuscular phenotype, but no electrophysiology or muscle pathology is reported, so neuromuscular involvement is not established. As a single case, it extends the TRPV4 variant spectrum but cannot establish genotype-phenotype correlations or treatment effects. | Metatropic dysplasia is a rare condition in which bones grow abnormally, causing short limbs and a spine that curves more and more over time. This report follows one girl with the condition from babyhood to age 7 and finds a new change in her TRPV4 gene that her parents did not have. She also developed very weak legs, which the authors think may mean her nerves or muscles are affected too, but they did not do nerve tests to check this. She had spinal surgery at age 5 and could later walk with braces. | TRPV4 is like a door that lets calcium into cells, and a change in it can affect how bones grow. This girl had a new change in her door gene, and her bones and spine grew in an unusual way. Her legs became very weak too, but the doctors did not test her nerves, so we do not know why. |
| #93The Zinc-Finger Domain Containing Protein ZC4H2 Interacts with TRPV4, Enhancing Channel Activity and Turnover at the Plasma MembraneVangeel 2020 Read the full analysis | Using a MAPPIT two-hybrid screen with the TRPV4 N terminus (amino acids 1 to 466) as bait, the authors identified ZC4H2 as a TRPV4 interactor and confirmed binding by co-immunoprecipitation in HEK-293T cells. Co-expressed ZC4H2 raised basal intracellular calcium and enhanced TRPV4 responses to arachidonic acid, 4α-PDD and hypotonic swelling, without affecting TRPV3 or altering TRPV4 mRNA, total protein or steady-state surface levels. TIR-FRAP suggested faster TRPV4 delivery to and retrieval from the plasma membrane. No disease-causing TRPV4 variants were tested. | TRPV4 does not work alone: other proteins attach to it and change how it behaves. This team searched thousands of human proteins and found one called ZC4H2 that sticks to the inside end of TRPV4. In kidney-derived cells grown in a dish, adding ZC4H2 made TRPV4 let in more calcium and made TRPV4 move on and off the cell surface faster. They did not test any of the TRPV4 changes that cause disease, so any link to CMT2C is still unknown. | TRPV4 is like a door that lets calcium into a cell. The scientists found a helper protein, ZC4H2, that makes the door let more calcium through and get swapped in and out faster, at least in cells in a dish. They have not yet checked whether this matters for CMT2C. |
| #94Recent advances in the genetics of hereditary axonal sensory-motor neuropathies type 2Ajroud-Driss 2011 Read the full analysis | This review summarizes the expanding genetics of autosomal dominant and recessive CMT2, with more than 10 genes defining subtypes CMT2A to CMT2N, the CMT2C/SPSMA gene being the most recently identified. The authors note that despite distinct functions, some CMT2 genes converge on common biological pathways relevant to pathogenesis. Its coverage of CMT2C cannot be judged from the abstract. | This article reviews what was known about the genes behind axonal CMT, the type where the long nerve fibers themselves are damaged. More than 10 genes had been found, and the one causing CMT2C was the newest. Some of these genes seem to work in the same processes inside the cell, which may help scientists understand the disease. | There are many kinds of CMT, and each is caused by a different gene, like different keys for different locks. This article lists them, and the gene for CMT2C was the newest one found when it was written. |
| #95Charcot-Marie-Tooth disease (CMT): distinctive phenotypic and genotypic features in CMT type 2Gemignani 2001 Read the full analysis | This review proposes a phenotypic classification of CMT2 into classical CMT2, atypical variants and complex 'CMT2 plus' forms, and surveys the genotypes then recognized, including CMT2C, defined by vocal cord paresis and listed without a mapped locus. The authors note an imperfect correspondence between genotypes and clinical subtypes. Its specific treatment of CMT2C cannot be judged from the abstract. | This article sorts the axonal type of CMT, CMT2, into groups based on symptoms, and lists the genetic types known at the time. CMT2C is listed as the type that comes with weakness of the vocal cords. The authors say finding more genes should help explain why the nerves are damaged. | Doctors tried to sort the different kinds of CMT2 into groups, like sorting books onto shelves. CMT2C went on the shelf for the kind that can make the voice weak. |
| #96Respiratory muscle weakness in peripheral neuropathiesBurakgazi 2010 Read the full analysis | This review notes that diaphragmatic weakness is uncommon in most peripheral neuropathies but is described in Guillain-Barré syndrome and in certain CMT subtypes, including CMT2C and CMT4B1. Electrophysiological findings generally do not correlate with respiratory signs or spirometry, except for the amplitudes of evoked phrenic nerve responses. The authors recommend structured respiratory assessment and suggest applying Guillain-Barré ventilation criteria to other neuropathies, though the evidence base cannot be judged from the abstract. | This article reviews breathing muscle weakness in nerve diseases. Most nerve diseases do not weaken the diaphragm, the main breathing muscle, but some types of CMT, including CMT2C, have been linked to diaphragm weakness. The usual nerve tests often do not show how well someone is breathing, apart from tests of the nerve that runs to the diaphragm. | The diaphragm is a muscle under your lungs that works like a pump to help you breathe. In a few kinds of CMT, including CMT2C, this pump can get weak, so doctors check breathing carefully. |
| #97The genetics of spinal muscular atrophiesWee 2010 Read the full analysis | This review summarizes clinical and genetic characterization of at least 16 spinal muscular atrophies, with genes identified for 14, including TRPV4, ATP7A, VRK1 and HSPB3 in the preceding year. It also covers preclinical therapeutic advances in proximal SMA using gene therapy, antisense oligonucleotides and small molecules. Its specific coverage of TRPV4 cannot be judged from the abstract. | This article reviews the many inherited conditions in which the motor nerve cells that control muscles are lost. TRPV4 was one of several genes newly linked to these conditions at the time. The treatment progress described was for a different, more common form, not for TRPV4 disease. | There are many kinds of spinal muscular atrophy, and TRPV4 was one of the genes newly found to cause some of them when this article was written. |
| #98Molecular genetics and mechanisms of disease in distal hereditary motor neuropathies: insights directing future genetic studiesDrew 2011 Read the full analysis | This review describes 11 causative genes for distal hereditary motor neuropathies, including TRPV4, and five further loci, and outlines emerging shared pathogenic mechanisms such as impaired axonal transport, RNA processing defects, protein aggregation, disrupted calcium channel activity and loss of neuroprotective signaling. It highlights genetic overlap between dHMN, CMT2 and SMA. Its treatment of TRPV4 cannot be judged from the abstract. | This article reviews inherited conditions that weaken muscles by damaging the motor nerves, with little or no effect on feeling. It lists 11 genes known to cause them, including TRPV4, and describes several ways these genes may damage nerves, one being problems with channels that let calcium into cells. Some of the same genes also cause types of CMT. | Some genes, including TRPV4, can make the nerves that move muscles stop working well. Scientists are still finding out exactly how this happens. |
| #99Distal hereditary motor neuropathiesTazir 2024 Read the full analysis | This review of distal hereditary motor neuropathies notes that more than 30 genes are implicated, yet around 60 to 70% of cases remain genetically uncharacterized, with prevalence estimates of 2.14 and 2.3 per 100,000. TRPV4 is cited among autosomal dominant genes overlapping with CMT2 and, with SLC5A7 and DCTN1, as a cause of dHMN with vocal cord palsy. Coverage of TRPV4 cannot be judged from the abstract. | This article reviews inherited conditions that slowly weaken muscles by damaging motor nerves, without affecting feeling. More than 30 genes are involved, but most people with these conditions still have no genetic answer. TRPV4 is one of three genes linked to the form that also weakens the vocal cords, and it is also a cause of CMT2. | Some inherited nerve conditions make muscles weak but do not change how things feel. TRPV4 is one of the genes that can cause the kind that also makes the voice weak. |
| #100Adult-onset spinal muscular atrophy: An updateJuntas Morales 2017 Read the full analysis | This review summarizes clinical features and pathophysiology of adult-onset genetic SMA with identified genes, including SMN1-related SMA, Kennedy disease, CHCHD10, TRPV4, DYNC1H1 and BICD2, and discusses progressive muscular atrophy as a likely ALS variant. Therapeutic trials are mentioned only for SMN1-related SMA and Kennedy disease. Its coverage of TRPV4 cannot be judged from the abstract. | This article reviews inherited conditions in which the motor nerve cells that control muscles are lost, starting in adulthood. TRPV4 is one of six genes it covers. The new treatments it mentions are for other, more common forms, not for TRPV4 disease. | Some people's muscles get weak as adults because the nerve cells that move them stop working. TRPV4 is one of several genes that can cause this. |
| #101[Experience in molecular diagnostic in hereditary neuropathies in a pediatric tertiary hospital]Fernández-Ramos 2015 Read the full analysis | In a retrospective series of 36 pediatric CMT patients from one tertiary center (2003-2015), CMT1A due to PMP22 duplication was the most frequent diagnosis (44%), and 12 patients remained without a molecular diagnosis. One child with multiple congenital arthrogryposis and vocal cord paralysis had a TRPV4 mutation and a phenotype of congenital spinal muscular atrophy with mild distal axonal neuropathy, and the mother had a scapuloperoneal syndrome. Selection, methods and the specific variant cannot be assessed from the abstract. | Doctors looked back at the records of 36 children with CMT seen at one specialist hospital between 2003 and 2015. The most common type was CMT1A. One child, born with stiff joints and paralyzed vocal cords, had a change in the TRPV4 gene, and the child's mother had weakness of the shoulder and lower leg muscles. | A children's hospital checked which CMT genes its young patients had. Many had the most common type, and one child had a change in the TRPV4 gene, which can cause CMT2C. |
| #102Molecular basis of axonal dysfunction and traffic impairments in CMTGentil 2012 Read the full analysis | This review examines whether genes causing axonal CMT, including MFN2, KIF1B, DYNC1H1, Rab7, TRPV4, NEFL and HSPB1, converge on impaired intracellular trafficking and mitochondrial dynamics. Only KIF1B and DYNC1H1 are directly linked to axonal transport, and the authors present a shared trafficking defect as a possible common mechanism rather than an established one. Evidence specific to TRPV4 cannot be judged from the abstract. | Nerve fibers are very long, and cells must move materials and mitochondria, the cell's energy-makers, along them. This review asks whether the many different genes that cause axonal CMT, including TRPV4, all disrupt this transport. The authors present this as a possible common link, not a proven one. | Long nerves need a delivery system to move supplies from one end to the other, like trains on a long track. Scientists think many CMT genes might upset this delivery system, but they are not sure yet. |
| #173Autosomal dominant congenital spinal muscular atrophy: a true form of spinal muscular atrophy caused by early loss of anterior horn cellsOates 2012 Read the full analysis | In a four-generation family with autosomal dominant congenital SMA, TRPV4 was excluded by haplotype analysis and sequencing, and known dominant SMA, distal HMN and CMT loci by linkage. Autopsy of a 14-month-old proband showed reduced anterior horn cells in the lumbosacral and, less so, cervical cord with atrophic ventral roots, but normal dorsal roots and normal sural, phrenic and tibial nerves. The absence of active neuronal degeneration led the authors to conclude that anterior horn cell loss occurs early and is largely complete by the end of infancy. These conclusions rest on a single autopsy in a family whose causative gene is unknown. | This study looked at a family with a rare inherited condition in which children have weak, wasted leg muscles and stiff joints from birth or early childhood. The family's condition was not caused by TRPV4 or by other known genes for similar conditions. When one affected baby died of an unrelated infection, an examination after death showed that she had fewer of the spinal cord nerve cells that control muscles, while the nerves that carry feeling looked normal. As there were no signs of ongoing damage, the authors think the nerve cells were lost early in life, though this is based on one child. | In this family, children have weak legs from very early in life. Looking at one child's spine after she died of an unrelated illness showed that some of the nerve cells that tell leg muscles to move were missing. It looked as if they were lost early, like a wall built with some bricks missing rather than bricks falling out later. The cause was not the TRPV4 gene. |
| #174Linkage mapping of the gene for Charcot-Marie-Tooth disease type 2 to chromosome 1p (CMT2A) and the clinical features of CMT2ASaito 1997 Read the full analysis | Linkage analysis in two Japanese CMT2 families gave a maximum cumulative multipoint LOD score of 3.69 at D1S244, assigning them to CMT2A on 1p35-36, with CMT2B and CMT2D excluded. CMT2C is cited only as a CMT2 form then unlinked to any known locus. | Researchers traced the cause of CMT in two Japanese families to a region of chromosome 1 known as the CMT2A region. The paper mentions that the gene region for CMT2C had not been found at the time. | This study found which part of the DNA caused CMT in two families, and it was a different kind of CMT from CMT2C. |
| #175Charcot-Marie-Tooth disease: experience from a large Italian tertiary neuromuscular centerGentile 2020 Read the full analysis | In a retrospective single-center cohort of 566 CMT patients followed between 1994 and 2016, 352 (62.19%) received a genetic diagnosis, with PMP22 duplication (CMT1A) the most frequent (51.13%). TRPV4 mutations were identified in 2 patients. Testing strategy and selection cannot be assessed from the abstract. | Doctors in Sicily looked back at the records of 566 people with CMT treated at their center over 22 years. Of these, 352 got a genetic diagnosis, and the most common type by far was CMT1A. Only 2 people had a change in the TRPV4 gene. | A big hospital looked at which CMT genes its patients had. Very few, only 2 people, had a change in the TRPV4 gene, so this kind of CMT is uncommon there. |
| #176Frequent genes in rare diseases: panel-based next generation sequencing to disclose causal mutations in hereditary neuropathiesDohrn 2017 Read the full analysis | A customized next generation sequencing panel applied to 612 index patients with hereditary neuropathies identified at least one putative pathogenic mutation in 121 (19.8%), most often in PMP22, GJB1, MPZ, SH3TC2 and MFN2. TRPV4 was among the less frequent genes with likely or known pathogenic variants. The authors judge panel sequencing time- and cost-effective, though the abstract gives no cost data. | Researchers used a test that reads many neuropathy genes at once in 612 people with inherited nerve conditions. A likely cause was found in 121 of them. TRPV4 was one of the less common genes found. | Doctors used a test that checks lots of nerve genes at once, like searching many drawers at the same time. A few people had a change in TRPV4, but most answers were in other genes. |