title: GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome.
abstract: Pallister-Hall syndrome (PHS, M146510) was first described in 1980 in six newborns. It is a pleiotropic disorder of human development that comprises hypothalamic hamartoma, central polydactyly, and other malformations. This disorder is inherited as an autosomal dominant trait and has been mapped to 7p13 (S. Kang et al. Autosomal dominant Pallister-Hall syndrome maps to 7p13. Am. J. Hum. Genet. 59, A81 (1996)), co-localizing the PHS locus and the GLI3 zinc finger transcription factor gene. Large deletions or translocations resulting in haploinsufficiency of the GLI3 gene have been associated with Greig cephalopolysyndactyly syndrome (GCPS; M175700) although no mutations have been identified in GCPS patients with normal karyotypes. Both PHS and GCPS have polysyndactyly, abnormal craniofacial features and are inherited in an autosomal dominant pattern, but they are clinically distinct. The polydactyly of GCPS is commonly preaxial and that of PHS is typically central or postaxial. No reported cases of GCPS have hypothalamic hamartoma and PHS does not cause hypertelorism or broadening of the nasal root or forehead. The co-localization of the loci for PHS and GCPS led us to investigate GLI3 as a candidate gene for PHS. Herein we report two PHS families with frameshift mutations in GLI3 that are 3' of the zinc finger-encoding domains, including one family with a de novo mutation. These data implicate mutations in GLI3 as the cause of autosomal dominant PHS, and suggest that frameshift mutations of the GLI3 transcription factor gene can alter the development of multiple organ systems in vertebrates.
authors.affiliation: Laboratory of Genetic Disease Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892-4472, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kang
authors.forename: J M
authors.initials: JM
authors.lastname: Graham
authors.forename: A H
authors.initials: AH
authors.lastname: Olney
authors.forename: L G
authors.initials: LG
authors.lastname: Biesecker
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000595:Amino Acid Sequence; D001483:Base Sequence; D002874:Chromosome Mapping; D002897:Chromosomes, Human, Pair 7; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D016368:Frameshift Mutation; D006222:Hamartoma / Q000235:genetics*; D006801:Humans; D007027:Hypothalamic Diseases / Q000235:genetics; D007231:Infant, Newborn; D051741:Kruppel-Like Transcription Factors; D008297:Male; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins; D010375:Pedigree; D017689:Polydactyly / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D018807:Polymorphism, Single-Stranded Conformational; D012097:Repressor Proteins; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics; D029867:Xenopus Proteins; D000074290:Zinc Finger Protein Gli3; D016335:Zinc Fingers
chemical_list: D004268:DNA-Binding Proteins; C108003:GLI3 protein, Xenopus; C065683:GLI3 protein, human; C465571:Gli3 protein, mouse; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D029867:Xenopus Proteins; D000074290:Zinc Finger Protein Gli3