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 funct...

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Bibliographic Details
Published in:Journal of molecular medicine (Berlin, Germany) Germany), 2011-01, Vol.89 (1), p.43-50
Main Authors: Ohta, Masaaki, Eguchi-Ishimae, Minenori, Ohshima, Mayumi, Iwabuki, Hidehiko, Takemoto, Koji, Murao, Kikuko, Chisaka, Toshiyuki, Yamamoto, Eiichi, Higaki, Takashi, Isoyama, Keiichi, Eguchi, Mariko, Ishii, Eiichi
Format: Article
Language:English
Subjects:
Animals
Base Sequence
Biological and medical sciences
Biomedical and Life Sciences
Biomedicine
Cell Culture Techniques
Cercopithecus aethiops
COS Cells
DNA-Binding Proteins - metabolism
GATA3 Transcription Factor - genetics
GATA3 Transcription Factor - metabolism
Gene Expression Profiling
Gene Expression Regulation
General aspects
Genes, Dominant
Hearing Loss, Sensorineural - genetics
HEK293 Cells
Human Genetics
Humans
Hypoparathyroidism - genetics
Infant, Newborn
Internal Medicine
Male
Medical sciences
Molecular Medicine
Molecular Sequence Data
Mutant Proteins - genetics
Mutation, Missense - genetics
Nephrosis - genetics
Original Article
Transcriptional Activation
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Summary: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.
ISSN:0946-2716
1432-1440
DOI:10.1007/s00109-010-0702-6