title: Dominant TRPV4 mutations in nonlethal and lethal metatropic dysplasia.
abstract: Metatropic dysplasia is a clinical heterogeneous skeletal dysplasia characterized by short extremities, a short trunk with progressive kyphoscoliosis, and craniofacial abnormalities that include a prominent forehead, midface hypoplasia, and a squared-off jaw. Dominant mutations in the gene encoding TRPV4, a calcium permeable ion channel, were identified all 10 of a series of metatropic dysplasia cases, ranging in severity from mild to perinatal lethal. These data demonstrate that the lethal form of the disorder is dominantly inherited and suggest locus homogeneity in the disease. Electrophysiological studies demonstrated that the mutations activate the channel, indicating that the mechanism of disease may result from increased calcium in chondrocytes. Histological studies in two cases of lethal metatropic dysplasia revealed markedly disrupted endochondral ossification, with reduced numbers of hypertrophic chondrocytes and presence of islands of cartilage within the zone of primary mineralization. These data suggest that altered chondrocyte differentiation in the growth plate leads to the clinical findings in metatropic dysplasia.
authors.affiliation: Department of Orthopedic Surgery, University of California at Los Angeles, Los Angeles, CA 90048, USA.
authors.forename: Natalia
authors.initials: N
authors.lastname: Camacho
authors.forename: Deborah
authors.initials: D
authors.lastname: Krakow
authors.forename: Sharlin
authors.initials: S
authors.lastname: Johnykutty
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Katzman
authors.forename: Samuel
authors.initials: S
authors.lastname: Pepkowitz
authors.forename: Joris
authors.initials: J
authors.lastname: Vriens
authors.forename: Bernd
authors.initials: B
authors.lastname: Nilius
authors.forename: Brendan F
authors.initials: BF
authors.lastname: Boyce
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Cohn
mesh_terms: D001848:Bone Diseases, Developmental / Q000235:genetics*; D001842:Bone and Bones / Q000473:pathology; D002356:Cartilage / Q000473:pathology; D002460:Cell Line; D005799:Genes, Dominant / Q000235:genetics*; D006801:Humans; D015640:Ion Channel Gating / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D050916:TRPV Cation Channels / Q000737:chemistry / Q000235:genetics*; D014132:Trachea / Q000473:pathology
chemical_list: D050916:TRPV Cation Channels; C416986:TRPV4 protein, human