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Published on: August 15, 2019
CMT2C with vocal cord paresis associated with short stature and mutations in the TRPV4 gene
1Department of Neurology, University of Washington Medical School, Seattle, WA, USA.
Background:
Recently, mutations in the transient receptor potential cation channel, subfamily V, member 4 gene (TRPV4) have been reported in Charcot-Marie-Tooth Type 2C (CMT2C) with vocal cord paresis. Other mutations in this same gene have been described in separate families with various skeletal dysplasias. Further clarification is needed of the different phenotypes associated with this gene.
Methods:
We performed clinical evaluation, electrophysiology, and genetic analysis of the TRPV4 gene in 2 families with CMT2C.
Results:
Two multigenerational families had a motor greater than sensory axonal neuropathy associated with variable vocal cord paresis. The vocal cord paresis varied from absent to severe, requiring permanent tracheotomy in 2 subjects. One family with mild neuropathy also manifested pronounced short stature, more than 2 SD below the average height for white Americans. There was one instance of dolichocephaly. A novel S542Y mutation in the TRPV4 gene was identified in this family. The other family had a more severe, progressive, motor neuropathy with sensory loss, but less remarkable short stature and an R315W mutation in TRPV4. Third cranial nerve involvement and sleep apnea occurred in one subject in each family.
Conclusion:
CMT2C with axonal neuropathy, vocal cord paresis, and short stature is a unique syndrome associated with mutations in the TRPV4 gene. Mutations in TRPV4 can cause abnormalities in bone, peripheral nerve, or both and may result in highly variable orthopedic and neurologic phenotypes.
Insights
Mutations in the TRPV4 gene cause Charcot-Marie-Tooth Type 2C (CMT2C), leading to axonal neuropathy, vocal cord paresis, and short stature. This gene impacts bone and nerve development, resulting in diverse phenotypes.
Area of Science:
- Genetics
- Neurology
- Orthopedics
Background:
- Mutations in the TRPV4 gene are linked to Charcot-Marie-Tooth Type 2C (CMT2C) with vocal cord paresis.
- Other TRPV4 mutations cause various skeletal dysplasias.
- Phenotypic variability associated with TRPV4 mutations requires further clarification.
Purpose of the Study:
- To investigate the clinical, electrophysiological, and genetic characteristics of TRPV4 mutations in families with CMT2C.
- To elucidate the spectrum of phenotypes associated with TRPV4 gene mutations.
Main Methods:
- Clinical evaluation
- Electrophysiology
- Genetic analysis of the TRPV4 gene in two CMT2C families.
Main Results:
- Two families presented with motor-dominant axonal neuropathy and variable vocal cord paresis.
- One family exhibited short stature and a novel S542Y TRPV4 mutation; the other had a progressive neuropathy and an R315W TRPV4 mutation.
- Cranial nerve involvement and sleep apnea were observed in individual subjects.
Conclusions:
- Charcot-Marie-Tooth Type 2C (CMT2C) with axonal neuropathy, vocal cord paresis, and short stature is a distinct syndrome caused by TRPV4 mutations.
- TRPV4 mutations can affect bone and peripheral nerves, leading to diverse orthopedic and neurological phenotypes.
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