title: The phenotypic spectrum of GLI3 morphopathies includes autosomal dominant preaxial polydactyly type-IV and postaxial polydactyly type-A/B; No phenotype prediction from the position of GLI3 mutations.
abstract: Functional characterization of a gene often requires the discovery of the full spectrum of its associated phenotypes. Mutations in the human GLI3 gene have been identified in Greig cepalopolysyndactyly, Pallister-Hall syndrome (PHS), and postaxial polydactyly type-A (PAP-A). We studied the involvement of GLI3 in additional phenotypes of digital abnormalities in one family (UR003) with preaxial polydactyly type-IV (PPD-IV), three families (UR014, UR015, and UR016) with dominant PAP-A/B (with PPD-A and -B in the same family), and one family with PHS. Linkage analysis showed no recombination with GLI3-linked polymorphisms. Family UR003 had a 1-nt frameshift insertion, resulting in a truncated protein of 1,245 amino acids. A frameshift mutation due to a 1-nt deletion was found in family UR014, resulting in a truncated protein of 1,280 amino acids. Family UR015 had a nonsense mutation, R643X, and family UR016 had a missense mutation, G727R, in a highly conserved amino acid of domain 3. The patient with PHS had a nonsense mutation, E1147X. These results add two phenotypes to the phenotypic spectrum caused by GLI3 mutations: the combined PAP-A/B and PPD-IV. These mutations do not support the suggested association between the mutations in GLI3 and the resulting phenotypes. We propose that all phenotypes associated with GLI3 mutations be called "GLI3 morphopathies," since the phenotypic borders of the resulting syndromes are not well defined and there is no apparent genotype-phenotype correlation.
authors.affiliation: Division of Medical Genetics, University of Geneva Medical School, Geneva, Switzerland.
authors.forename: U
authors.initials: U
authors.lastname: Radhakrishna
authors.forename: D
authors.initials: D
authors.lastname: Bornholdt
authors.forename: H S
authors.initials: HS
authors.lastname: Scott
authors.forename: U C
authors.initials: UC
authors.lastname: Patel
authors.forename: C
authors.initials: C
authors.lastname: Rossier
authors.forename: H
authors.initials: H
authors.lastname: Engel
authors.forename: A
authors.initials: A
authors.lastname: Bottani
authors.forename: D
authors.initials: D
authors.lastname: Chandal
authors.forename: J L
authors.initials: JL
authors.lastname: Blouin
authors.forename: J V
authors.initials: JV
authors.lastname: Solanki
authors.forename: K H
authors.initials: KH
authors.lastname: Grzeschik
authors.forename: S E
authors.initials: SE
authors.lastname: Antonarakis
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D003062:Codon / Q000235:genetics; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005091:Exons / Q000235:genetics; D005192:Family Health; D005260:Female; D005799:Genes, Dominant / Q000235:genetics*; D008040:Genetic Linkage / Q000235:genetics; D005838:Genotype; D006801:Humans; D007194:India; D051741:Kruppel-Like Transcription Factors; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins; D010375:Pedigree; D010641:Phenotype; D017689:Polydactyly / Q000235:genetics* / Q000503:physiopathology; D011110:Polymorphism, Genetic / Q000235:genetics; D012097:Repressor Proteins; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D029867:Xenopus Proteins; D000074290:Zinc Finger Protein Gli3
chemical_list: D003062:Codon; 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