title: Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia.
abstract: The brachyolmias constitute a clinically and genetically heterogeneous group of skeletal dysplasias characterized by a short trunk, scoliosis and mild short stature. 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 4alpha-phorbol 12,13-didecanoate (4alphaPDD). This study thus defines a previously unknown mechanism, activation of a calcium-permeable TRP ion channel, in skeletal dysplasia pathogenesis.
authors.affiliation: Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Rock
authors.forename: Jean
authors.initials: J
authors.lastname: Prenen
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Funari
authors.forename: Tara L
authors.initials: TL
authors.lastname: Funari
authors.forename: Barry
authors.initials: B
authors.lastname: Merriman
authors.forename: Stanley F
authors.initials: SF
authors.lastname: Nelson
authors.forename: Ralph S
authors.initials: RS
authors.lastname: Lachman
authors.forename: William R
authors.initials: WR
authors.lastname: Wilcox
authors.forename: Soraya
authors.initials: S
authors.lastname: Reyno
authors.forename: Roberto
authors.initials: R
authors.lastname: Quadrelli
authors.forename: Alicia
authors.initials: A
authors.lastname: Vaglio
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Owsianik
authors.forename: Annelies
authors.initials: A
authors.lastname: Janssens
authors.forename: Thomas
authors.initials: T
authors.lastname: Voets
authors.forename: Shiro
authors.initials: S
authors.lastname: Ikegawa
authors.forename: Toshiro
authors.initials: T
authors.lastname: Nagai
authors.forename: David L
authors.initials: DL
authors.lastname: Rimoin
authors.forename: Bernd
authors.initials: B
authors.lastname: Nilius
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Cohn
mesh_terms: D001848:Bone Diseases, Developmental / Q000000981:diagnostic imaging / Q000235:genetics*; D002460:Cell Line; D005260:Female; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D011859:Radiography; D050916:TRPV Cation Channels / Q000235:genetics* / Q000378:metabolism*
chemical_list: D050916:TRPV Cation Channels; C416986:TRPV4 protein, human