Title: Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia
Authors: Rock, Matthew J ×
Prenen, Jean
Funari, Vincent A
Funari, Tara L
Merriman, Barry
Nelson, Stanley F
Lachman, Ralph S
Wilcox, William R
Reyno, Soraya
Quadrelli, Roberto
Vaglio, Alicia
Owsianik, Grzegorz
Janssens, Annelies
Voets, Thomas
Ikegawa, Shiro
Nagai, Toshiro
Rimoin, David L
Nilius, Bernd
Cohn, Daniel H #
Issue Date: Aug-2008
Publisher: Nature publishing group
Series Title: Nature Genetics vol:40 issue:8 pages:999-1003
Abstract: 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.
ISSN: 1061-4036
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Ion Channel Research
Department of Cellular and Molecular Medicine - miscellaneous
× corresponding author
# (joint) last author

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