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TRPV4-associated skeletal dysplasias


  • Gen Nishimura,

  • Ekkehart Lausch,

  • Ravi Savarirayan,

  • Masahiro Shiba,

  • Juergen Spranger,

  • Bernhard Zabel,

  • Shiro Ikegawa,

  • Andrea Superti-Furga,

  • Sheila Unger

    Corresponding author
    • Génétique Médicale, CHUV, Av. Decker 2, 1011 Lausanne, Switzerland.
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  • Gen Nishimura and Ekkehart Lausch contributed equally to this study.

  • How to cite this article: Nishimura G, Lausch E, Savarirayan R, Shiba M, Spranger J, Zabel B, Ikegawa S, Superti-Furga A, Unger S. 2012. TRPV4-associated skeletal dysplasias. Am J Med Genet Part C Semin Med Genet.


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. © 2012 Wiley Periodicals, Inc.