Journal
JOURNAL OF BONE AND MINERAL RESEARCH
Volume 29, Issue 8, Pages 1815-1822Publisher
WILEY-BLACKWELL
DOI: 10.1002/jbmr.2220
Keywords
TRPV4; METATROPIC DYSPLASIA; SMDK; SKELETAL DYSPLASIA; CALCIUM CHANNEL; TRANSGENIC MICE
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Funding
- NICHD/NIH [HD22657]
- Orthopaedic Hospital Research Center at UCLA
- NIH [5 T32 AR 59033-2]
- BCM Intellectual and Developmental Disabilities Research Center from the Eunice Kennedy Shriver National Institute of Child Health & Human Development [HD024064]
- Rolanette and Berdon Lawrence Bone Disease Program of Texas
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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. (C) 2014 American Society for Bone and Mineral Research
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