期刊
NATURE GENETICS
卷 42, 期 2, 页码 165-U102出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.509
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资金
- National Institute of Neurological Disorders and Stroke [NS050641]
- Les Turner ALS Foundation
- Vena E. Schaff ALS Research Fund
- Harold Post Research Professorship
- Herbert and Florence C. Wenske Foundation
- David C. Asselin MD Memorial Fund
- Help America Foundation
- Les Turner ALS Foundation/Herbert C. Wenske Foundation
- Epilepsy Foundation
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(1,2). We mapped SPSMA and CMT2C risk loci to 12q24.1-q24.31 with an overlapping region between the two diseases(3,4). Further analysis reduced the CMT2C risk locus to a 4-Mb region(5). 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.
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