Spinal muscular atrophies (SMA, also known as hereditary motor neuropathies) and hereditary motor and sensory neuropathies (HMSN) are clinically and genetically heterogeneous disorders of the peripheral nervous system. Here we report that mutations in the TRPV4 gene cause congenital © 2009 Nature America, Inc. All rights reserved.Correspondence should be addressed to M.A.-G. (michaela.auergrumbach@medunigraz.at).. METHODS: Methods and any associated references are available in the online version of the paper at http://www.nature.com/ naturegenetics/. Accession codes. GenBank: human TRPV4 cDNA, NM_021625; human TRPV4, NP_067638 IsoA. Pfam: ankyrin repeat, PF00023.Note: Supplementary information is available on the Nature Genetics website. AUTHOR CONTRIBUTIONS: M.A.-G., S.U., J.S., M.E.M., A.H.C., K.J.D., C.M.A.v.R.-A., N.E.A., H.L., B.S.-W., R.P., C.L., G.W.P., H.J.S., H.K. and T.R.P. recruited the study participants, acquired clinical data, conducted neurological and neurophysiological evaluations and performed linkage analysis. M.A.-G, C.G., L.P. and C.F. carried out the Affymetrix array linkage studies and identified the mutations. A.O., Z.B. and B.T. designed, carried out and analyzed the electrophysiological and Ca 2+ -imaging studies. E.F. conducted immunofluorescence and immunohistochemistry studies. H.S. conducted fluorescence-activated cell sorting (FACS) and biotinylation studies. A.K. performed structural biology and biocomputing analyses. A.H.C., M.E.M. and H.K. participated in the data analysis and reviewed the manuscript. M.A.-G. and C.G. analyzed the data, designed and supervised the study and wrote the manuscript. Supplementary Fig. 1) and observed linkage to three chromosomal regions with log 10 of odds (lod) scores >2 for several SNP markers, including the chromosome 12q23-24 region (data not shown). We constructed haplotypes by including additional distantly related family members (right branch of the pedigree; Supplementary Fig. 1). The genetic interval transmitted with the disease resides between SNPs rs2374688 and rs35426 (Chr. 12: 106,197,054,429 bp; Supplementary Table 1) and overlaps with the intervals reported for risk of congenital distal SMA, SPSMA and HMSN2C 2-4 .
Europe PMC Funders GroupIn an affected individual from family FAM_1, we began sequencing all protein-coding exons and exon-intron boundaries of 19 genes but initially observed only known SNPs (Supplementary Table 2). However, sequencing of all protein-coding exons of TRPV4 (transient receptor potential vanilloid 4; chr. 12: 108,705,277-108,755,595; reverse strand) revealed a heterozygous C-to-T nucleotide change at position 943 in exon 6 (Supplementary Fig. 2a), which is predicted to cause the substitution of arginine with tryptophan at position 315 of TRPV4 (R315W). We then screened DNA samples from additional families showing one of the phenotypes described above, including two families previously reported 1,3,4 . All affected individuals from the chromosome 12q23-24-linked family (here called FAM_2) described by...
