Knobloch syndrome: Novel mutations in COL18A1, evidence for genetic heterogeneity, and a functionally impaired polymorphism in endostatin

Authors

  • Olivier Menzel,

    1. Division of Medical Genetics, University of Geneva Medical School and University Hospital of Geneva, Geneva, Switzerland
    Current affiliation:
    1. Swiss Institute for Experimental Cancer Research (ISREC), ch. des Boveresses 155, 1066 Epalinges sur Lausanne, Switzerland
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    • Olivier Menzel, Reidunn C.J. Bekkeheien, and Alexandre Reymond contributed equally to this work.

  • Reidunn C.J. Bekkeheien,

    1. Department of Cell Biology, Harvard Medical School, Boston, Massachusetts
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    • Olivier Menzel, Reidunn C.J. Bekkeheien, and Alexandre Reymond contributed equally to this work.

  • Alexandre Reymond,

    1. Division of Medical Genetics, University of Geneva Medical School and University Hospital of Geneva, Geneva, Switzerland
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    • Olivier Menzel, Reidunn C.J. Bekkeheien, and Alexandre Reymond contributed equally to this work.

  • Naomi Fukai,

    1. Department of Cell Biology, Harvard Medical School, Boston, Massachusetts
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  • Eileen Boye,

    1. Department of Cell Biology, Harvard Medical School, Boston, Massachusetts
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  • Gyorgy Kosztolanyi,

    1. Department of Medical Genetics, University of Pécs, Pécs, Hungary
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  • Salim Aftimos,

    1. Northern Regional Genetics Service, Department of Clinical Genetics, Starship Children's Hospital, Auckland, New Zealand
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  • Samuel Deutsch,

    1. Division of Medical Genetics, University of Geneva Medical School and University Hospital of Geneva, Geneva, Switzerland
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  • Hamish S. Scott,

    1. Division of Medical Genetics, University of Geneva Medical School and University Hospital of Geneva, Geneva, Switzerland
    Current affiliation:
    1. Genetics and Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Royal Parade, Parkville, 3052 Australia
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  • Bjorn R. Olsen,

    1. Department of Cell Biology, Harvard Medical School, Boston, Massachusetts
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  • Stylianos E. Antonarakis,

    Corresponding author
    1. Division of Medical Genetics, University of Geneva Medical School and University Hospital of Geneva, Geneva, Switzerland
    • Division of Medical Genetics, University of Geneva Medical School and University Hospital of Geneva, CMU, 1, Rue Michel Servet, 1211 Geneva, Switzerland
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  • Michel Guipponi

    1. Division of Medical Genetics, University of Geneva Medical School and University Hospital of Geneva, Geneva, Switzerland
    Current affiliation:
    1. Genetics and Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Royal Parade, Parkville, 3052 Australia
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  • Communicated by Peter Byers

Abstract

Knobloch syndrome (KNO) is an autosomal recessive disorder characterized by high myopia, vitreoretinal degeneration with retinal detachment, and congenital encephalocele. Pathogenic mutations in the COL18A1 gene on 21q22.3 were recently identified in KNO families. Analysis of two unrelated KNO families from Hungary and New Zealand allowed us to confirm the involvement of COL18A1 in the pathogenesis of KNO and to demonstrate the existence of genetic heterogeneity. Two COL18A1 mutations were identified in the Hungarian family: a 1-bp insertion causing a frameshift and a premature in-frame stop codon and an amino acid substitution. This missense variant is located in a conserved amino acid of endostatin, a cleavage product of the carboxy-terminal domain of collagen alpha 1 XVIII. D1437N (D104N in endostatin) likely represents a pathogenic mutation, as we show that the endostatin N104 mutant is impaired in its affinity towards laminin. Linkage to the COL18A1 locus was excluded in the New Zealand family, providing evidence for the existence of a second KNO locus. We named the second unmapped locus for Knobloch syndrome KNO2. Mutation analysis excluded COL15A1, a member of the multiplexin collagen subfamily similar to COL18A1, as being responsible for KNO2. Hum Mutat 23:77–84, 2004. © 2003 Wiley-Liss, Inc.

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