Abstract
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.
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Acknowledgements
The authors thank Ms. Risa Sogabe, Dr. Wen Ming, and Dr. Wu Zhou Ying for technical assistance. This work was supported by a Grant-in-Aid for Scientific Research and a Grant-in-Aid for Cancer Research from the Ministry of Health and Labor, Japan.
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M. Ohta and M. Eguchi-Ishimae contributed equally to this study.
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Ohta, M., Eguchi-Ishimae, M., Ohshima, M. et al. Novel dominant-negative mutant of GATA3 in HDR syndrome. J Mol Med 89, 43–50 (2011). https://doi.org/10.1007/s00109-010-0702-6
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DOI: https://doi.org/10.1007/s00109-010-0702-6