Spondyloepiphyseal dysplasia, Omani type: Further definition of the phenotype

Authors

  • Mirjam H.H. van Roij,

    1. Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands
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  • Shuji Mizumoto,

    1. Laboratory of Proteoglycan Signaling and Therapeutics, Faculty of Advanced Life Science, Hokkaido University Graduate School of Life Science, Sapporo, Japan
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  • Shuhei Yamada,

    1. Laboratory of Proteoglycan Signaling and Therapeutics, Faculty of Advanced Life Science, Hokkaido University Graduate School of Life Science, Sapporo, Japan
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  • Tim Morgan,

    1. Department of Paediatrics and Child Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
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  • M.B. Tan-Sindhunata,

    1. Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands
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  • H. Meijers-Heijboer,

    1. Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands
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  • J.I.L.M. Verbeke,

    1. Department of Radiology, VU University Medical Center, Amsterdam, The Netherlands
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  • David Markie,

    1. Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
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  • Kazuyuki Sugahara,

    Corresponding author
    1. Laboratory of Proteoglycan Signaling and Therapeutics, Faculty of Advanced Life Science, Hokkaido University Graduate School of Life Science, Sapporo, Japan
    • Laboratory of Proteoglycan Signaling and Therapeutics, Frontier Research Center for Post-Genomic Science and Technology, Hokkaido University Graduate School of Life Science, Nishi 11-choume, Kita 21-jo, Kita-ku, Sapporo, Hokkaido 001-0021, Japan.
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  • Stephen P. Robertson

    Corresponding author
    1. Department of Paediatrics and Child Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
    • Department of Paediatrics and Child Health, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand.
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  • How to cite this article: van Roij MHH, Mizumoto S, Yamada S, Morgan T, Tan-Sindhunata MB, Meijers-Heijboer H, Verbeke JILM, Markie D, Sugahara K, Robertson SP. 2008. Spondyloepiphyseal dysplasia, Omani type: Further definition of the phenotype. Am J Med Genet Part A 146A:2376–2384.

  • M.H.H. van Roij and S. Mizumoto contributed equally to this work.

Abstract

Spondyloepiphyseal dysplasia (SED), Omani type (OMIM 608637) is a recessively inherited skeletal dysplasia previously described in two distantly related families from the Republic of Oman. The phenotype consists of short stature, severe kyphoscoliosis, arthritic joints (elbows, wrists, knees), secondary large joint dislocations, rhizomelia, fusion of carpal bones and mild brachydactyly. Affected individuals were homozygous for a missense mutation, R304Q in CHST3 that encodes the enzyme chondroitin 6-O-sulfotransferase-1 (C6ST-1). This enzyme mediates the sulfation of proteoglycans, particularly chondroitin sulfate (CS), in the extracellular matrix of cartilage. Here we describe the identification of a mutation (857T > C predicting the substitution L286P) in CHST3 in a Turkish family and extend the clinical phenotype of SED-Omani type to include congenital joint dislocation, club feet, ventricular septal defect, deafness, metacarpal shortening and accessory carpal ossification centers. Fibroblasts and urine obtained from affected patients demonstrated negligible levels of 6-O-sulfated GalNAc residue in CS. Furthermore, the 6-O-sulfotransferase activity of cloned C6ST-1 into which the L286P mutation had been introduced was dramatically reduced, confirming the pathogenicity of this substitution. These results indicate that the clinical consequences of a deficiency of 6-O-sulfation in CS can be varied and that a clinical spectrum may exist similar to that seen in other skeletal dysplasias characterized by disorders of proteoglycan sulfation. © 2008 Wiley-Liss, Inc.

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