Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4

Han Xiang Deng*, Christopher J. Klein, Jianhua Yan, Yong Shi, Yanhong Wu, Faisal Fecto, Hau Jie Yau, Yi Yang, Hong Zhai, Nailah Siddique, E. Tessa Hedley-Whyte, Robert Delong, Marco Martina, Peter J. Dyck, Teepu Siddique

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

182 Scopus citations

Abstract

Scapuloperoneal spinal muscular atrophy (SPSMA) and hereditary motor and sensory neuropathy type IIC (HMSN IIC, also known as HMSN2C or Charcot-Marie-Tooth disease type 2C (CMT2C)) are phenotypically heterogeneous disorders involving topographically distinct nerves and muscles. We originally described a large New England family of French-Canadian origin with SPSMA and an American family of English and Scottish descent with CMT2C. We mapped SPSMA and CMT2C risk loci to 12q24.1-q24.31 with an overlapping region between the two diseases. Further analysis reduced the CMT2C risk locus to a 4-Mb region. Here we report that SPSMA and CMT2C are allelic disorders caused by mutations in the gene encoding the transient receptor potential cation channel, subfamily V, member 4 (TRPV4). Functional analysis revealed that increased calcium channel activity is a distinct property of both SPSMA-and CMT2C-causing mutant proteins. Our findings link mutations in TRPV4 to altered calcium homeostasis and peripheral neuropathies, implying a pathogenic mechanism and possible options for therapy for these disorders.

Original languageEnglish (US)
Pages (from-to)165-169
Number of pages5
JournalNature Genetics
Volume42
Issue number2
DOIs
StatePublished - Feb 2010

ASJC Scopus subject areas

  • Genetics

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