Truncating loss-of-function mutations of <Emphasis Type="Italic">DISP1</Emphasis> contribute to holoprosencephaly-like microform features in humans |
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Authors: | Erich Roessler Yong Ma Maia V Ouspenskaia Felicitas Lacbawan Claude Bendavid Christèle Dubourg Philip A Beachy Maximilian Muenke |
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Institution: | (1) 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, USA;(2) Laboratoire de Génétique Moléculaire, CHU Pontchaillou, IFR 140, Rennes, France;(3) Génétique et Développement, Université de Rennes 1, IFR 140, Rennes, France;(4) Johns Hopkins University, Baltimore, USA;(5) Present address: Stanford University, Stanford, USA |
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Abstract: | Defective function of the Sonic Hedgehog (SHH) signaling pathway is the most frequent alteration underlying holoprosencephaly
(HPE) or its various clinical microforms. We performed an extensive mutational analysis of the entire human DISP1 gene, required for secretion of all hedgehog ligand(s) and which maps to the HPE 10 locus of human chromosome 1q41, as a
HPE candidate gene. Here, we describe two independent families with truncating mutations in human DISP1 that resemble the cardinal craniofacial and neuro-developmental features of a recently described microdeletion syndrome that
includes this gene; therefore, we suggest that DISP1 function contributes substantially to both of these signs in humans. While these clinical features are consistent with common
HPE microforms, especially those linked to defective signaling by Sonic Hedgehog, we have insufficient evidence so far that
functionally abnormal DISP1 alleles will commonly contribute to the more severe features of typical HPE. |
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