title: Mutations in the C-terminal domain of Sonic Hedgehog cause holoprosencephaly.
abstract: Holoprosencephaly (HPE) is the most common brain anomaly in humans, involving abnormal formation and septation of the developing central nervous system. Among the heterogeneous causes of HPE, mutations in the Sonic Hedgehog (SHH) gene have been shown to result in an autosomal dominant form of the disorder. Here we describe a total of five different mutations in the processing domain encoded by exon 3 of SHH in familial and sporadic HPE. This is the first instance in humans where SHH mutations in the domain responsible for autocatalytic cleavage and cholesterol modification of the N-terminal signaling domain of the protein have been observed.
authors.affiliation: Children's Hospital of Philadelphia, Division of Human Genetics and Molecular Biology, University of Pennsylvania School of Medicine, Philadelphia 19104-4399, USA.
authors.forename: E
authors.initials: E
authors.lastname: Roessler
authors.forename: E
authors.initials: E
authors.lastname: Belloni
authors.forename: K
authors.initials: K
authors.lastname: Gaudenz
authors.forename: F
authors.initials: F
authors.lastname: Vargas
authors.forename: S W
authors.initials: SW
authors.lastname: Scherer
authors.forename: L C
authors.initials: LC
authors.lastname: Tsui
authors.forename: M
authors.initials: M
authors.lastname: Muenke
mesh_terms: D000409:Alanine / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D002461:Cell Line, Transformed; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D005799:Genes, Dominant; D018698:Glutamic Acid / Q000235:genetics; D005998:Glycine / Q000235:genetics; D053823:Hedgehog Proteins; D016142:Holoprosencephaly / Q000209:etiology / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D017354:Point Mutation; D011506:Proteins / Q000235:genetics*; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid; D012694:Serine / Q000235:genetics; D013912:Threonine / Q000235:genetics; D015534:Trans-Activators; D014633:Valine / Q000235:genetics
chemical_list: D053823:Hedgehog Proteins; D011506:Proteins; C509239:SHH protein, human; D015534:Trans-Activators; D013912:Threonine; D018698:Glutamic Acid; D012694:Serine; D014633:Valine; D000409:Alanine; D005998:Glycine