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: Han-Xiang Deng, Christopher J Klein, Jianhua Yan, Yong Shi, Yanhong Wu, Faisal Fecto, Hau-Jie Yau, Yi Yang, Hong Zhai, Nailah Siddique, E Tessa Hedley-Whyte, Robert Delong, Marco Martina, Peter J Dyck, Teepu Siddique
• Journal: Nature genetics (Nat Genet) Vol. 42 Issue 2 Pg. 165-9 (Feb 2010) ISSN: 1546-1718 [Electronic] United States
• PMID: 20037587 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Hypotonic Solutions
• Mutant Proteins
• TRPV Cation Channels
• TRPV4 protein, human

Topics

• Alleles
• Amino Acid Sequence
• Base Sequence
• Cell Line
• Cell Membrane (drug effects, metabolism)
• Charcot-Marie-Tooth Disease (complications, genetics, physiopathology)
• DNA Mutational Analysis
• Female
• Humans
• Hypotonic Solutions (pharmacology)
• Ion Channel Gating (drug effects)
• Male
• Molecular Sequence Data
• Muscular Atrophy, Spinal (complications, genetics, pathology, physiopathology)
• Mutant Proteins (metabolism)
• Mutation (genetics)
• Pedigree
• Protein Transport (drug effects)
• TRPV Cation Channels (chemistry, genetics)
• Transfection