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

Divison of Nephrology (A.Z., K.W., N.H., Y.P.), Department of Medicine, University Health Network and University of Toronto, Toronto, Ontario, Canada M5G2C4; Academic Endocrine Unit (A.M.N., A.A., R.V.T.), Nuffield Department of Medicine, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford OX3 7LJ, United Kingdom; and Renal Unit of General Regional Hospital "G. Papanikolaou" (M.S., G.B., K.S.), Thessaloniki, Greece

Address all correspondence and requests for reprints to: York Pei, M.D., 13 EN-228, 200 Elizabeth Street, Toronto, Ontario, Canada M5G2C4. 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 Friend 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 a nonconservative change of a single amino acid (R276P) in the ZnF1 domain. Functional analysis using dissociation electrophoretic mobility shift 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 a result of GATA3 haploinsufficiency.

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