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

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

doi:10.1038/ng.509

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.

Highlights

SPSMA is characterized by progressive scapuloperoneal atrophy and weakness, laryngeal palsy, congenital absence of muscles and developmental abnormalities of the bones[1]
Because the entire 4-Mb CMT2C-linked region is included in the 14-Mb SPSMA-linked region and SPSMA and CMT2C share some common clinical features, including characteristic vocal cord paresis[1,2,3,4,5], we considered that SPSMA and CMT2C may be clinical variants of the same genetic entity
In the SPSMAaffected family, the R316C-causing substitution in TRPV4 was the only genetic defect we found in the coding exons of all the genes within the minimum region shared by both the SPSMA and CMT2C loci

Summary

Introduction

SPSMA is characterized by progressive scapuloperoneal atrophy and weakness, laryngeal palsy, congenital absence of muscles and developmental abnormalities of the bones[1]. In the SPSMAaffected family, the R316C-causing substitution in TRPV4 was the only genetic defect we found in the coding exons of all the genes within the minimum region shared by both the SPSMA and CMT2C loci. Analysis of TRPV4 revealed a heterozygous mutation, G806A, leading to R269H, in exon 5 of the TRPV4 gene in this large CMT2C pedigree (Fig. 2c).

Results

Conclusion