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 |
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| Authors: | Erich Roessler Kenia B. El‐Jaick Christèle Dubourg Jorge I. Vélez Benjamin D. Solomon Daniel E. Pineda‐álvarez Felicitas Lacbawan Nan Zhou Maia Ouspenskaia Aimée Paulussen Hubert J. Smeets Ute Hehr Claude Bendavid Sherri Bale Sylvie Odent Véronique David Maximilian Muenke |
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| Affiliation: | 1. Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA;2. In the authors' opinion these individuals contributed equally to this work.;3. Laboratoire de Génétique Moléculaire, CHU Pontchaillou, Rennes Cedex, France;4. CNRS UMR6061 Génétique et Développement, Université de Rennes 1, IFR140, France;5. Academic Hospital and Department of Clinical Genetics, University of Maastricht, The Netherlands;6. Center for Human Genetics and Department of Human Genetics, University of Regensburg, Germany;7. GeneDx, Gaithersburg, MD, USA;8. Service de génétique clinique,CHU H?pital Sud, Rennes, France |
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| 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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| Keywords: | holoprosencephaly mutation spectrum SHH protein processing |
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