title: 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.
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.
authors: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors: Erich
authors: E
authors: Roessler
authors: Kenia B
authors: KB
authors: El-Jaick
authors: Christèle
authors: C
authors: Dubourg
authors: Jorge I
authors: JI
authors: Vélez
authors: Benjamin D
authors: BD
authors: Solomon
authors: Daniel E
authors: DE
authors: Pineda-Alvarez
authors: Felicitas
authors: F
authors: Lacbawan
authors: Nan
authors: N
authors: Zhou
authors: Maia
authors: M
authors: Ouspenskaia
authors: Aimée
authors: A
authors: Paulussen
authors: Hubert J
authors: HJ
authors: Smeets
authors: Ute
authors: U
authors: Hehr
authors: Claude
authors: C
authors: Bendavid
authors: Sherri
authors: S
authors: Bale
authors: Sylvie
authors: S
authors: Odent
authors: Véronique
authors: V
authors: David
authors: Maximilian
authors: M
authors: Muenke
mesh_terms: D000595:Amino Acid Sequence; D053823:Hedgehog Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016142:Holoprosencephaly / Q000235:genetics*; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid
chemical_list: D053823:Hedgehog Proteins; D008024:Ligands; C509239:SHH protein, human