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Updated: May 20, 2026
Yeast Luminometric and Xenopus Oocyte Electrophysiological Examinations of the Molecular Mechanosensitivity of TRPV4
Published on: December 31, 2013
TRPV4-associated skeletal dysplasias
Gen Nishimura1, Ekkehart Lausch, Ravi Savarirayan
1Génétique Médicale, CHUV, Av. Decker 2, 1011 Lausanne, Switzerland.
Abstract:
Dominant mutations in the TRPV4 gene result in a bone dysplasia family and form a continuous phenotypic spectrum that includes, in decreasing severity, lethal, and nonlethal metatropic dysplasia (MD), spondylometaphyseal dysplasia Kozlowski type (SMDK), and autosomal dominant brachyolmia. Several rare variant phenotypes that have some overlap but deviate in some ways from the general pattern have also been described. The known variant phenotypes are spondyloepiphyseal dysplasia Maroteaux type (Pseudo-Morquio type 2), parastremmatic dysplasia, and familial digital arthropathy with brachydactyly. Interestingly, different TRPV4 mutations have been associated with dominantly inherited neurologic disorders such as congenital spinal muscular atrophy and hereditary motor and sensory neuropathy. Finally, a small number of patients have been identified in whom a TRPV4 mutation results in a phenotype combining skeletal dysplasia with peripheral neuropathy. The TRPV4 gene encodes a regulated calcium channel implicated in multiple and diverse cellular processes. Over 50 different TRPV4 mutations have been reported, with two codons appearing to be mutational hot spots: P799 in exon 15, mostly associated with MD, and R594 in exon 11, associated with SMDK. While most pathogenic mutations tested so far result in activation of the calcium channel in vitro, the mechanisms through which TRPV4 activation results in skeletal dysplasia and/or peripheral neuropathy remain unclear and the genotype-phenotype correlations in this group of disorders remains somewhat mysterious. Since the phenotypic expression of most mutations seems to be relatively constant, careful clinical and radiographic assessment is useful in directing molecular analysis.
Insights
Dominant mutations in the TRPV4 gene cause a spectrum of bone dysplasias and can also lead to neurological disorders. Understanding these TRPV4 gene mutations is key to diagnosing and potentially treating these rare conditions.
Area of Science:
- Genetics
- Molecular Biology
- Skeletal Dysplasias
Background:
- Dominant mutations in the TRPV4 gene are linked to a range of skeletal dysplasias, including metatropic dysplasia (MD) and spondylometaphyseal dysplasia Kozlowski type (SMDK).
- TRPV4 gene variants have also been associated with distinct neurological conditions, such as congenital spinal muscular atrophy and hereditary motor and sensory neuropathy.
- Some patients present with a combined phenotype of skeletal dysplasia and peripheral neuropathy, highlighting the diverse roles of TRPV4.
Purpose of the Study:
- To summarize the phenotypic spectrum associated with dominant TRPV4 mutations.
- To highlight the association of TRPV4 variants with both skeletal and neurological disorders.
- To discuss the current understanding and remaining questions regarding genotype-phenotype correlations in TRPV4-related conditions.
Main Methods:
- Review of existing literature on TRPV4 mutations and associated phenotypes.
- Analysis of reported genotype-phenotype correlations.
- In vitro studies on calcium channel function (mentioned as context for ongoing research).
Main Results:
- Over 50 TRPV4 mutations identified, with specific codons (P799 and R594) as mutational hotspots.
- Established phenotypic spectrum includes lethal/nonlethal MD, SMDK, and autosomal dominant brachyolmia, with rare variant phenotypes also described.
- TRPV4 mutations can cause skeletal dysplasia, peripheral neuropathy, or a combination of both.
Conclusions:
- TRPV4 mutations lead to a complex spectrum of skeletal and neurological disorders.
- While many mutations activate the calcium channel, the precise mechanisms causing disease remain unclear.
- Clinical and radiographic assessment can guide molecular genetic analysis for suspected TRPV4-related disorders.
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