Résumé :
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Mutations in the Transient Receptor Potential Vanilloid subtype 4 (TRPV4) gene, that encodes a Ca2+ permeable non-selective cation channel, have been recently associated with a broad spectrum of inherited neurological and orthopedic diseases. Four heterozygous distinct hotspot mutations (R232C, R269H, R315W, and R316C) all targeting conserved arginine residues and affecting the intracellular N-terminal ankyrin domain of the TRPV4 ion channel, have been shown to cause nonprogressive congenital distal spinal muscular atrophy (dSMA), scapuloperoneal muscular dystrophy (SPSMA), and / or hereditary motor and sensory neuropathy type 2C (HMSN2C). The age of onset varied widely, ranging from congenital to late adulthood onset. Additional features such as vocal cord paralysis and skeletal dysplasias were frequently observed in patients carrying one of these mutations. In the majority of patients nerve conduction studies revealed a predominantly motor neuropathy with axonal characteristics. Also incomplete penetrance has been reported. Interestingly, these diverse phenotypes were observed even within one family thus suggesting considerable phenotypic variation of the disease. Moreover, several further mutations in TRPV4 have been identified in autosomal dominant skeletal dysplasias that cause varying degrees of short trunk and short limbs ranging from the relatively mild type 3 brachyolmia, Kozlowski spondylomethaphyseal dysplasia (SMDK) and the more severe metatropic dysplasia. The heterogeneous spectrum of phenotypes and diagnostic clues of this new hereditary channelopathy elicited by mutations in TRPV4 will be discussed.
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