Novel dominant-negative mutant of GATA3 in HDR syndrome.
HDR syndrome is an autosomal dominant disorder characterized by hypoparathyroidism, sensorineural deafness, and renal anomaly caused by mutation of the GATA3 gene located at chromosome 10p15. We report the case of a neonate with HDR syndrome and a novel GATA3 mutation. We performed genetic and functional analysis of GATA3 in this patient and identified a novel heterozygous 1516G> C missense mutation in exon 5, resulting in a cysteine-to-serine substitution at codon 321 (Cys321Ser). Mutated and wild-type GATA3 proteins were expressed at a similar level in vitro, indicating that the mutated GATA3 protein was stable. Luciferase assay revealed that the Cys321Ser-mutated GATA3 lacked transactivation activity due to loss of DNA-binding activity as confirmed by gel shift assay. Moreover, mutated GATA3 exerted a dominant-negative effect over the transactivation activity of wild-type GATA3. These findings indicate that not only haploinsufficiency of GATA3 but also the dominant-negative effect of Cys321Ser-mutated GATA3 might have been responsible for the HDR syndrome phenotype of our patient.
Department of Neonatology, Maternity & Perinatal Care Unit, Ehime University Hospital, Shitsukawa, Toon, Matsuyama, Ehime, 791-0295, Japan.
Masaaki
M
Ohta
Minenori
M
Eguchi-Ishimae
Mayumi
M
Ohshima
Hidehiko
H
Iwabuki
Koji
K
Takemoto
Kikuko
K
Murao
Toshiyuki
T
Chisaka
Eiichi
E
Yamamoto
Takashi
T
Higaki
Keiichi
K
Isoyama
Mariko
M
Eguchi
Eiichi
E
Ishii
D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D018929:Cell Culture Techniques; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000378:metabolism; D050990:GATA3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D057809:HEK293 Cells; D006319:Hearing Loss, Sensorineural / Q000235:genetics; D006801:Humans; D007011:Hypoparathyroidism / Q000235:genetics; D007231:Infant, Newborn; D008297:Male; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000235:genetics; D020125:Mutation, Missense / Q000235:genetics; D009401:Nephrosis / Q000235:genetics; D015533:Transcriptional Activation
D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D050505:Mutant Proteins