The mutational spectrum of holoprosencephaly-associated changes within the SHH gene in humans predicts loss-of-function through either key structural alterations of the ligand or its altered synthesis

Authors

  • Erich Roessler,

    1. Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
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    • In the authors' opinion these individuals contributed equally to this work.

  • Kenia B. El-Jaick,

    1. Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
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    • In the authors' opinion these individuals contributed equally to this work.

  • Christèle Dubourg,

    1. Laboratoire de Génétique Moléculaire, CHU Pontchaillou, Rennes Cedex, France
    2. CNRS UMR6061 Génétique et Développement, Université de Rennes 1, IFR140, France
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    • In the authors' opinion these individuals contributed equally to this work.

  • Jorge I. Vélez,

    1. Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
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  • Benjamin D. Solomon,

    1. Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
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  • Daniel E. Pineda-Álvarez,

    1. Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
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  • Felicitas Lacbawan,

    1. Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
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  • Nan Zhou,

    1. Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
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  • Maia Ouspenskaia,

    1. Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
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  • Aimée Paulussen,

    1. Academic Hospital and Department of Clinical Genetics, University of Maastricht, The Netherlands
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  • Hubert J. Smeets,

    1. Academic Hospital and Department of Clinical Genetics, University of Maastricht, The Netherlands
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  • Ute Hehr,

    1. Center for Human Genetics and Department of Human Genetics, University of Regensburg, Germany
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  • Claude Bendavid,

    1. Laboratoire de Génétique Moléculaire, CHU Pontchaillou, Rennes Cedex, France
    2. CNRS UMR6061 Génétique et Développement, Université de Rennes 1, IFR140, France
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  • Sherri Bale,

    1. GeneDx, Gaithersburg, MD, USA
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  • Sylvie Odent,

    1. CNRS UMR6061 Génétique et Développement, Université de Rennes 1, IFR140, France
    2. Service de génétique clinique,CHU Hôpital Sud, Rennes, France
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  • Véronique David,

    1. Laboratoire de Génétique Moléculaire, CHU Pontchaillou, Rennes Cedex, France
    2. CNRS UMR6061 Génétique et Développement, Université de Rennes 1, IFR140, France
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  • Maximilian Muenke

    Corresponding author
    1. Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
    • Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, 35 Convent Drive, MSC 3717, Building 35, Room 1B-203, Bethesda, MD 20892-3717
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  • This article is a US Government work and, as such, is in the public domain in the United States of America.

  • Communicated by Ravi Savarirayan

Abstract

Mutations within either the SHH gene or its related pathway components are the most common, and best understood, pathogenetic changes observed in holoprosencephaly patients; this fact is consistent with the essential functions of this gene during forebrain development and patterning. Here we summarize the nature and types of deleterious sequence alterations among over one hundred distinct mutations in the SHH gene (64 novel mutations) and compare these to over a dozen mutations in disease-related Hedgehog family members IHH and DHH. This combined structural analysis suggests that dysfunction of Hedgehog signaling in human forebrain development can occur through truncations or major structural changes to the signaling domain, SHH-N, as well as due to defects in the processing of the mature ligand from its pre-pro-precursor or defective post-translation bi-lipid modifications with palmitate and cholesterol Published 2009 by Wiley-Liss, Inc.

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