title: Mice expressing mutant Trpv4 recapitulate the human TRPV4 disorders.
abstract: Activating mutations in transient receptor potential vanilloid family member 4 (Trpv4) are known to cause a spectrum of skeletal dysplasias ranging from autosomal dominant brachyolmia to lethal metatropic dysplasia. To develop an animal model of these disorders, we created transgenic mice expressing either wild-type or mutant TRPV4. Mice transgenic for wild-type Trpv4 showed no morphological changes at embryonic day 16.5 but did have a delay in bone mineralization. Overexpression of a mutant TRPV4 caused a lethal skeletal dysplasia that phenocopied many abnormalities associated with metatropic dysplasia in humans, including dumbbell-shaped long bones, a small ribcage, abnormalities in the autopod, and abnormal ossification in the vertebrae. The difference in phenotype between embryos transgenic for wild-type or mutant Trpv4 demonstrates that an increased amount of wild-type protein can be tolerated and that an activating mutation of this protein is required to produce a skeletal dysplasia phenotype.
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, Orthopaedic Hospital Research Center, University of California, Los Angeles, CA 90095.|Department of Orthopaedic Surgery and Orthopaedic Hospital Research Center, University of California, Los Angeles, CA 90095.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Weinstein
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, Orthopaedic Hospital Research Center, University of California, Los Angeles, CA 90095.
authors.forename: Stuart W
authors.initials: SW
authors.lastname: Tompson
authors.affiliation: Howard Hughes Medical Institute and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Howard Hughes Medical Institute and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030.
authors.forename: Brendan
authors.initials: B
authors.lastname: Lee
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, Orthopaedic Hospital Research Center, University of California, Los Angeles, CA 90095.|Department of Orthopaedic Surgery and Orthopaedic Hospital Research Center, University of California, Los Angeles, CA 90095.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Cohn
mesh_terms: D000818:Animals; D001846:Bone Development / Q000235:genetics; D001848:Bone Diseases, Developmental / Q000235:genetics*; D019902:Chondrocytes / Q000378:metabolism; D015870:Gene Expression; D030342:Genetic Diseases, Inborn; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D050916:TRPV Cation Channels / Q000235:genetics* / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D050916:TRPV Cation Channels
keywords: CALCIUM CHANNEL; METATROPIC DYSPLASIA; SKELETAL DYSPLASIA; SMDK; TRANSGENIC MICE; TRPV4