Journal
HUMAN MUTATION
Volume 30, Issue 10, Pages E921-E935Publisher
WILEY
DOI: 10.1002/humu.21090
Keywords
holoprosencephaly; mutation spectrum; SHH; protein processing
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Funding
- National Human Genome Research Institute, National Institutes of Health
- GIS Institut des Maladies Rares
- COREC (CHU, Faculte de Medecine, Rennes, France)
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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 (C) 2009 WileyLiss, Inc.
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