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Disruption of human limb morphogenesis by a dominant negative mutation in CDMP1

Nature Genetics volume 17, pages 58–64 (1997)Cite this article

Abstract

Chondrodysplasia Grebe type (CGT) is an autosomal recessive disorder characterized by severe limb shortening and dysmorphogenesis. We have identified a causative point mutation in the gene encoding the bone morphogenetic protein (BMP)–like molecule, cartilage-derived morphogenetic protein–1 (CDMP-1). The mutation substitutes a tyrosine for the first of seven highly conserved cysteine residues in the mature active domain of the protein. We demonstrate that the mutation results in a protein that is not secreted and is inactive in vitro. It produces a dominant negative effect by preventing the secretion of other, related BMP family members. We present evidence that this may occur through the formation of heterodimers. The mutation and its proposed mechanism of action provide the first human genetic indication that composite expression patterns of different BMPs dictate limb and digit morphogenesis.

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Authors and Affiliations

  1. Craniofacial and Skeletal Diseases Branch, National Institute of Dental Research, National Institutes of Health, Bethesda, Maryland, 20892, USA

    J. Terrig Thomas, Kerning Lin, Ludwig Erlacher & Frank P. Luyten

  2. Department of Pediatrics, University of Connecticut Health Center, Farmington, Connecticut, 06030, USA

    Michael W. Kilpatrick, Peter Lembessis & Petros Tsipouras

  3. Department of Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada

    Teresa Costa

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  1. J. Terrig Thomas
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Correspondence to J. Terrig Thomas.

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Thomas, J., Kilpatrick, M., Lin, K. et al. Disruption of human limb morphogenesis by a dominant negative mutation in CDMP1. Nat Genet 17, 58–64 (1997). https://doi.org/10.1038/ng0997-58

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