Novel dominant-negative mutant of GATA3 in HDR syndrome
| Autor: | Eiichi Yamamoto, Hidehiko Iwabuki, Minenori Eguchi-Ishimae, Mariko Eguchi, Toshiyuki Chisaka, Koji Takemoto, Kikuko Murao, Takashi Higaki, Keiichi Isoyama, Eiichi Ishii, Masaaki Ohta, Mayumi Ohshima |
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| Rok vydání: | 2010 |
| Předmět: |
Male
Transcriptional Activation Hypoparathyroidism Hearing Loss Sensorineural Molecular Sequence Data Cell Culture Techniques Mutation Missense GATA3 Transcription Factor Biology medicine.disease_cause Transactivation Exon Chlorocebus aethiops Drug Discovery medicine Animals Humans Missense mutation Electrophoretic mobility shift assay Gene Genetics (clinical) Genes Dominant Mutation Base Sequence Gene Expression Profiling Infant Newborn GATA3 Molecular biology DNA-Binding Proteins HEK293 Cells Gene Expression Regulation COS Cells Cancer research Nephrosis Molecular Medicine Mutant Proteins Haploinsufficiency |
| Zdroj: | Journal of Molecular Medicine. 89:43-50 |
| ISSN: | 1432-1440 0946-2716 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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