Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4.
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.
Deng
Han-Xiang
HX
Davee Department of Neurology and Clinical Neurosciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. h-deng@northwestern.edu
Klein
Christopher J
CJ
Yan
Jianhua
J
Shi
Yong
Y
Wu
Yanhong
Y
Fecto
Faisal
F
Yau
Hau-Jie
HJ
Yang
Yi
Y
Zhai
Hong
H
Siddique
Nailah
N
Hedley-Whyte
E Tessa
ET
Delong
Robert
R
Martina
Marco
M
Dyck
Peter J
PJ
Siddique
Teepu
T
D000483:Alleles; D000595:Amino Acid Sequence; D001483:Base Sequence; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002607:Charcot-Marie-Tooth Disease / Q000150:complications* / Q000235:genetics* / Q000503:physiopathology; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007038:Hypotonic Solutions / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects; D008297:Male; D008969:Molecular Sequence Data; D009134:Muscular Atrophy, Spinal / Q000150:complications* / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D021381:Protein Transport / Q000187:drug effects; D050916:TRPV Cation Channels / Q000737:chemistry / Q000235:genetics*; D014162:Transfection
D007038:Hypotonic Solutions; D050505:Mutant Proteins; D050916:TRPV Cation Channels; C416986:TRPV4 protein, human