CMT 2C: Scapuloperoneal spinal muscular atrophyand CMT2C are allelic disorders c

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Nat Genet. 2009 Dec 27.

CMT 2C: Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders

caused by alterations in TRPV4.

Deng HX, Klein CJ, Yan J, Shi Y, Wu Y, Fecto F, Yau HJ, Yang Y, Zhai H, Siddique

N, Hedley-Whyte ET, Delong R, a M, Dyck PJ, Siddique T.

Division of Neuromuscular Medicine, Davee Department of Neurology and Clinical

Neurosciences, Northwestern University Feinberg School of Medicine, Chicago,

Illinois, USA.

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 ish 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.