title: Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4.
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.
authors.affiliation: Davee Department of Neurology and Clinical Neurosciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. h-deng@northwestern.edu
authors.forename: Han-Xiang
authors.initials: HX
authors.lastname: Deng
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Klein
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yan
authors.forename: Yong
authors.initials: Y
authors.lastname: Shi
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Wu
authors.forename: Faisal
authors.initials: F
authors.lastname: Fecto
authors.forename: Hau-Jie
authors.initials: HJ
authors.lastname: Yau
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.forename: Hong
authors.initials: H
authors.lastname: Zhai
authors.forename: Nailah
authors.initials: N
authors.lastname: Siddique
authors.forename: E Tessa
authors.initials: ET
authors.lastname: Hedley-Whyte
authors.forename: Robert
authors.initials: R
authors.lastname: Delong
authors.forename: Marco
authors.initials: M
authors.lastname: Martina
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Dyck
authors.forename: Teepu
authors.initials: T
authors.lastname: Siddique
mesh_terms: 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
chemical_list: D007038:Hypotonic Solutions; D050505:Mutant Proteins; D050916:TRPV Cation Channels; C416986:TRPV4 protein, human