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Type VI collagen mutations in Bethlem myopathy, an autosomal dominant myopathy with contractures

Nature Geneticsvolume 14pages113115 (1996) | Download Citation

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Abstract

Among the diverse family of collagens, the widely expressed microfibrillar type VI collagen is believed to play a role in bridging cells with the extracellular matrix. Several observations imply substrate properties for cell attachment1 as well as association with major collagen fibers2. Previously, we have established genetic linkage between the genes encoding the three constituent α-chains of type VI collagen and Bethlem myopathy3–5. A distinctive feature of this autosomal dominant disorder consists of contractures of multiple joints in addition to generalized muscular weakness and wasting6–10. Nine kindreds show genetic linkage to the COL6A1–COL6A2 cluster on chromosome 21q22.3 (refs 3,4; manuscript submitted) whereas one family shows linkage to markers on chromosome 2q37 close to COL6A3 (ref. 5). Sequence analysis in four families reveals a mutation in COL6A1 in one and a COL6A2 mutation in two other kindreds. Both mutations disrupt the Gly-X-Y motif of the triple helical domain by substitution of Gly for either Val or Ser. Analogous to the putative perturbation of the anchoring function of the dystrophin-associated complex in congenital muscular dystrophy with mutations in the α2-subunit of laminin, our observations suggest a similar mechanism in Bethlem myopathy.

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Affiliations

  1. Department of Neurology, Academic Medical Center, P.O. Box 22700, 1100 DE, Amsterdam, The Netherlands

    • G. Joost Jöbsis
    • , H. Keizers
    • , Jeroen P. Vreijling
    • , Marianne de Visser
    • , Ruud A. Wolterman
    • , Frank Baas
    •  & Pieter A. Bolhuis
  2. Division of Neurology, Duke University Medical Center, P.O. Box 2900, Durham, North Carolina, 27710, USA

    • Marcy C. Speer

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https://doi.org/10.1038/ng0996-113

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