title: Elucidation of penetrance variability of a ZIC3 mutation in a family with complex heart defects and functional analysis of ZIC3 mutations in the first zinc finger domain.
abstract: We studied a series of 42 cases of transposition of the great arteries (TGA), a complex heart defect (CHD) that is two times more prevalent in males than in females. A mutation in the X chromosome at the ZIC3 gene was found in two affected siblings (one male, one female) and their unaffected mother. A second factor, skewed X-inactivation pattern explained the discrepancy between the daughter/mother phenotype. In this family, the missense mutation (p.W255G) was found in the first zinc finger of ZIC3, a domain that is relatively specific to each of the five human ZIC genes. It was tested further along with two other mutations of this domain (p.C253S and p.H286R). In transfected 3T3 cells, mutants p.W255G and p.H286R expressed lower protein levels, and an increased protein degradation (p.W255G only). Moreover, mutants p.C253S and p.W255G had a decreased transcription activation of the TK-luciferase reporter gene. Nuclear translocation of the three ZIC3 mutants varied considerably depending on the experimental models. Finally, p.W255G and p.H286R showed diminished activities for both left-right axis disturbance and neural crest induction in Xenopus embryos. These results suggest that mutations in the first zinc finger of ZIC3 mildly affect several functions of the protein.
authors.affiliation: INSERM, Equipe de Recherche Methodologique (ERM) 0107, Bron, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Chhin
authors.forename: Minoru
authors.initials: M
authors.lastname: Hatayama
authors.forename: Dominique
authors.initials: D
authors.lastname: Bozon
authors.forename: Miyuki
authors.initials: M
authors.lastname: Ogawa
authors.forename: Patric
authors.initials: P
authors.lastname: Schön
authors.forename: Takahide
authors.initials: T
authors.lastname: Tohmonda
authors.forename: François
authors.initials: F
authors.lastname: Sassolas
authors.forename: Jun
authors.initials: J
authors.lastname: Aruga
authors.forename: Anna-Gaëlle
authors.initials: AG
authors.lastname: Valard
authors.forename: Su-Chiung
authors.initials: SC
authors.lastname: Chen
authors.forename: Patrice
authors.initials: P
authors.lastname: Bouvagnet
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004252:DNA Mutational Analysis; D005260:Female; D006580:Genetic Carrier Screening; D040181:Genetic Diseases, X-Linked / Q000175:diagnosis / Q000235:genetics; D006330:Heart Defects, Congenital / Q000175:diagnosis / Q000235:genetics*; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D041681:NIH 3T3 Cells; D010375:Pedigree; D019683:Penetrance; D012737:Sex Factors; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D014162:Transfection; D014188:Transposition of Great Vessels / Q000235:genetics; D049951:X Chromosome Inactivation / Q000235:genetics; D014982:Xenopus laevis; D016335:Zinc Fingers / Q000235:genetics*
chemical_list: D018398:Homeodomain Proteins; D014157:Transcription Factors; C491595:ZIC3 protein, human