title: Functional analysis of a novel GATA3 mutation in a family with the hypoparathyroidism, deafness, and renal dysplasia syndrome.
abstract: The hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome is an autosomal dominant disorder caused by mutations of a member of the GATA-binding family of transcription factors, GATA3. This dual zinc finger transcription factor binds DNA with its C-terminal zinc finger (ZnF2) and stabilizes this binding with its N-terminal zinc finger (ZnF1). ZnF1 also interacts with other zinc finger proteins, notably Friend of GATA (FOG). The HDR syndrome has been described in patients with mutations affecting both ZnF1 and ZnF2 domains; the former result in inefficient interaction with FOG, and the latter result in disruption of DNA binding. We report a patient with renal failure, hypoparathyroidism, and bilateral hearing loss. Assessment of family members indicated that the disease arose as a de novo mutation in her mother. Analysis of GATA3 in the family revealed a heterozygous missense mutation resulting in a nonconservative change of a single amino acid (R276P) in the ZnF1 domain. Functional analysis using dissociation electrophoretic mobility shift and yeast two-hybrid assays showed reduced binding affinity to the GATA motifs but normal interaction with FOG in vitro. These results are consistent with the predicted functions of human GATA3-ZnF1 from three-dimensional molecular modeling and with HDR being a result of GATA3 haploinsufficiency.
authors.affiliation: Department of Nephrology, University Health Network, Toronto, Ontario, Canada M5G2C4.
authors.forename: Alireza
authors.initials: A
authors.lastname: Zahirieh
authors.forename: M Andrew
authors.initials: MA
authors.lastname: Nesbit
authors.forename: Asif
authors.initials: A
authors.lastname: Ali
authors.forename: Kairong
authors.initials: K
authors.lastname: Wang
authors.forename: Ning
authors.initials: N
authors.lastname: He
authors.forename: Maria
authors.initials: M
authors.lastname: Stangou
authors.forename: Gerasimos
authors.initials: G
authors.lastname: Bamichas
authors.forename: Kostas
authors.initials: K
authors.lastname: Sombolos
authors.forename: Rajesh V
authors.initials: RV
authors.lastname: Thakker
authors.forename: York
authors.initials: Y
authors.lastname: Pei
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D004268:DNA-Binding Proteins / Q000235:genetics*; D003638:Deafness / Q000235:genetics*; D050990:GATA3 Transcription Factor; D006801:Humans; D007011:Hypoparathyroidism / Q000235:genetics*; D007668:Kidney / Q000002:abnormalities*; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D013577:Syndrome; D015534:Trans-Activators / Q000235:genetics*; D020798:Two-Hybrid System Techniques
chemical_list: D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D015534:Trans-Activators