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This version published online on February 10, 2005
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2004-1969
A more recent version of this article appeared on April 1, 2005
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Submitted on October 5, 2004
Accepted on January 27, 2005

Functional Analysis of a Novel GATA3 Mutation in a Family with the Hypoparathyroidism, Deafness and Renal Dysplasia (HDR) Syndrome

Alireza Zahirieh, Andrew M. Nesbit, Asif Ali, Kairong Wang, Ning He, Maria Stangou, Gerasimos Bamichas, Kostas Sombolos, Rajesh V. Thakker, and York Pei*

Divison of Nephrology, Department of Medicine, University Health Network and University of Toronto, Toronto, Ontario, Canada; Academic Endocrine Unit, Nuffield Department of Medicine, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, United Kingdom; Renal Unit of General Regional Hospital "G. Papanikolaou", Thessaloniki, Greece

* To whom correspondence should be addressed. E-mail: york.pei{at}uhn.on.ca.

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 Friends 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 non-conservative change of a single amino acid (R276P) in the ZnF1 domain. Functional analysis using dissociation electrophoretic mobility shift (EMSA) 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 due to GATA3 haploinsufficiency.




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