Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia
| Autor: | Barry Merriman, Alicia Vaglio, Vincent Funari, Thomas Voets, Bernd Nilius, Tara L. Funari, William R. Wilcox, Ralph S. Lachman, Roberto Quadrelli, Grzegorz Owsianik, Stanley F. Nelson, Jean Prenen, Daniel H. Cohn, David L. Rimoin, Soraya Reyno, Annelies Janssens, Matthew J. Rock, Toshiro Nagai, Shiro Ikegawa |
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| Rok vydání: | 2008 |
| Předmět: |
Male
TRPV4 Agonist Candidate gene genetic-disorders medicine.drug_class chondrocytes Mutation Missense TRPV Cation Channels cation channel trpv4 Biology Article Cell Line Transient receptor potential channel dysplasia expression Genetics medicine skeleton Humans Bone Diseases Developmental Congenital distal spinal muscular atrophy Point mutation HEK 293 cells Autosomal dominant brachyolmia differentiation medicine.disease Molecular biology Pedigree Radiography modulation activation Female |
| Zdroj: | Nature Genetics. 40:999-1003 |
| ISSN: | 1546-1718 1061-4036 |
| Popis: | The brachyolmias constitute a clinically and genetically heterogeneous group of skeletal dysplasias characterized by a short trunk, scoliosis and mild short stature(1). Here, we identify a locus for an autosomal dominant form of brachyolmia on chromosome 12q24.1-12q24.2. Among the genes in the genetic interval, we selected TRPV4, which encodes a calcium permeable cation channel of the transient receptor potential (TRP) vanilloid family, as a candidate gene because of its cartilage-selective gene expression pattern. In two families with the phenotype, we identified point mutations in TRPV4 that encoded R616Q and V620I substitutions, respectively. Patch clamp studies of transfected HEK cells showed that both mutations resulted in a dramatic gain of function characterized by increased constitutive activity and elevated channel activation by either mechano-stimulation or agonist stimulation by arachidonic acid or the TRPV4-specific agonist 4 alpha-phorbol 12,13-didecanoate (4 alpha PDD). This study thus defines a previously unknown mechanism, activation of a calcium-permeable TRP ion channel, in skeletal dysplasia pathogenesis. ispartof: Nature Genetics vol:40 issue:8 pages:999-1003 ispartof: location:United States status: published |
| Databáze: | OpenAIRE |
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