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Dominant TRPV4 mutations in nonlethal and lethal metatropic dysplasia

Authors

  • Natalia Camacho,

    1. Department of Orthopedic Surgery, University of California at Los Angeles, Los Angeles, California
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  • Deborah Krakow,

    1. Department of Orthopedic Surgery, University of California at Los Angeles, Los Angeles, California
    2. Department of Human Genetics, University of California at Los Angeles, Los Angeles, California
    3. Department of Obstetrics and Gynecology, University of California at Los Angeles, Los Angeles, California
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  • Sharlin Johnykutty,

    1. Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York
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  • Philip J. Katzman,

    1. Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York
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  • Samuel Pepkowitz,

    1. Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California
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  • Joris Vriens,

    1. Department of Molecular Cell Biology, Laboratory Ion Channel Research, Campus Gasthuisberg, KU Leuven, Belgium
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  • Bernd Nilius,

    1. Department of Molecular Cell Biology, Laboratory Ion Channel Research, Campus Gasthuisberg, KU Leuven, Belgium
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  • Brendan F. Boyce,

    1. Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York
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  • Daniel H. Cohn

    Corresponding author
    1. Department of Human Genetics, University of California at Los Angeles, Los Angeles, California
    2. Department of Pediatrics David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California
    3. Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, California
    4. Department of Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California
    • Medical Genetics Institute, Metro 203, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048.
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  • How to cite this article: Camacho N, Krakow D, Johnykutty S, Katzman PJ, Pepkowitz S, Vriens J, Nilius B, Boyce BF, Cohn DH. 2010. Dominant TRPV4 mutations in nonlethal and lethal metatropic dysplasia. Am J Med Genet Part A 152A:1169–1177.

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. © 2010 Wiley-Liss, Inc.

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