A specific mutation in the distant sonic hedgehog (SHH) cis-regulator (ZRS) causes Werner mesomelic syndrome (WMS) while complete ZRS duplications underlie Haas type polysyndactyly and preaxial polydactyly (PPD) with or without triphalangeal thumb

Authors

  • Dagmar Wieczorek,

    Corresponding author
    1. Institut für Humangenetik, Universitätsklinikum Essen, Essen, Germany
    • Institut für Humangenetik, Universitätsklinikum Essen, Hufelandstr. 55, Essen 45122, Germany
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  • Barbara Pawlik,

    1. Institute for Human Genetics, University of Cologne, Cologne, Germany
    2. Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
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  • Yun Li,

    1. Institute for Human Genetics, University of Cologne, Cologne, Germany
    2. Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
    3. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
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  • Nurten A. Akarsu,

    1. Department of Medical Genetics, Hacettepe University Medical Faculty, Ankara, Turkey
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  • Almuth Caliebe,

    1. Institut für Humangenetik, Christian-Albrechts-Universität zu Kiel, Kiel, Germany
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  • Klaus J.W. May,

    1. Genomatix Software GmbH, München, Germany
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  • Bernd Schweiger,

    1. Pädiatrische Radiologie, Institut für Diagnostische und Interventionelle Radiologie und Neuroradiologie, Universitätsklinikum Essen, Essen, Germany
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  • Fernando R. Vargas,

    1. Genetics and Molecular Biology Department, Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro, Brazil
    2. Genetics Division, Instituto Nacional de Câncer, Rio de Janeiro, Brazil
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  • Sevim Balci,

    1. Clinical Genetics Unit, Hacettepe University Medical Faculty, Ankara, Turkey
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  • Gabriele Gillessen-Kaesbach,

    1. Institut für Humangenetik, Universitätsklinikum Essen, Essen, Germany
    2. Institut für Humangenetik, Universität zu Lübeck, Lübeck, Germany
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  • Bernd Wollnik

    Corresponding author
    1. Institute for Human Genetics, University of Cologne, Cologne, Germany
    2. Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
    3. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
    • Institute of Human Genetics, University of Cologne, Kerpener Str. 34, 50931 Cologne, Germany
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  • Communicated by Iain McIntosh

Abstract

Werner mesomelic syndrome (WMS) is an autosomal dominant disorder with unknown molecular etiology characterized by hypo- or aplasia of the tibiae in addition to the preaxial polydactyly (PPD) of the hands and feet and/or five-fingered hand with absence of thumbs. We show that point mutations of a specific nucleotide within the sonic hedgehog (SHH) regulatory region (ZRS) cause WMS. In a previously unpublished WMS family, we identified the causative G>A transition at position 404 of the ZRS, and in six affected family members of a second WMS family we found a 404G>C mutation of the ZRS. The 404G>A ZRS mutation is known as the “Cuban mutation” of PPD type II (PPD2). Interestingly, the index patient of that family had tibial hypoplasia as well. These data provide the first evidence that WMS is caused by a specific ZRS mutation, which leads to strong ectopic SHH expression. In contrast, we show that complete duplications of the ZRS region lead to type Haas polysyndactyly or triphalangeal thumb-polysyndactyly syndrome, but do not affect lower limb development. We suggest the term “ZRS-associated syndromes” and a clinical subclassification for the continuum of limb malformations caused by different molecular alterations of the ZRS. Hum Mutat 30:1–9, 2009. © 2009 Wiley-Liss, Inc.

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