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J. Biol. Chem., Vol. 279, Issue 21, 22624-22634, May 21, 2004

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Characterization of GATA3 Mutations in the Hypoparathyroidism, Deafness, and Renal Dysplasia (HDR) Syndrome^*

From the ^aAcademic Endocrine Unit, Nuffield Department of Medicine, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford OX3 7LJ, United Kingdom, the ^ePediatric and Reproductive Endocrinology Branch, National Institutes of Health, Bethesda, Maryland 20892-1284, the ^fDivision of Genetics, Department of Pediatrics, MetroHealth Medical Center, Cleveland, Ohio 44109, the ^gDepartment of Clinical Genetics, The Churchill Hospital, Oxford OX3 7L3, United Kingdom, the ^hDepartment of Chemical Pathology, The Guy's, King's College and St Thomas' Hospitals Medical and Dental School, St Thomas' Hospital, London SE1 7EH, United Kingdom, the ⁱDepartment of Endocrinology, Auckland Hospital, Park Rd., Auckland 1, New Zealand, the ^jDepartment of Pediatric Endocrinology, The Children's Hospital at The Cleveland Clinic, Cleveland, Ohio 44195-0001, the ^kDivisions of Hematology and Oncology, Mayo Clinic, Rochester, Minnesota 55905, the ^lPaediatric Renal Unit, Guy's Hospital, St Thomas Street, London SE1 9RT, United Kingdom, the ^mInstitute of Medical Genetics, University of Wales College of Medicine, Cardiff CF14 4XN, United Kingdom, and the ⁿDepartment of Nephrology, Morriston Hospital, Swansea SA6 6NL, United Kingdom

The hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome is an autosomal dominant disorder caused by mutations of the dual zinc finger transcription factor, GATA3. The C-terminal zinc finger (ZnF2) binds DNA, whereas the N-terminal finger (ZnF1) stabilizes this DNA binding and interacts with other zinc finger proteins, such as the Friends of GATA (FOG). We have investigated seven HDR probands and their families for GATA3 abnormalities and have identified two nonsense mutations (Glu-228 Stop and Arg-367 Stop); two intragenic deletions that result in frameshifts from codons 201 and 355 with premature terminations at codons 205 and 370, respectively; one acceptor splice site mutation that leads to a frameshift from codon 351 and a premature termination at codon 367; and two missense mutations (Cys-318 Arg and Asn-320 Lys). The functional effects of these mutations, together with a previously reported GATA3 ZnF1 mutation and seven other engineered ZnF1 mutations, were assessed by electrophoretic mobility shift, dissociation, yeast two-hybrid and glutathione S-transferase pull-down assays. Mutations involving GATA3 ZnF2 or adjacent basic amino acids resulted in a loss of DNA binding, but those of ZnF1 either lead to a loss of interaction with specific FOG2 ZnFs or altered DNA-binding affinity. These findings are consistent with the proposed three-dimensional model of ZnF1, which has separate DNA and protein binding surfaces. Thus, our results, which expand the spectrum of HDR-associated GATA3 mutations and report the first acceptor splice site mutation, help to elucidate the molecular mechanisms that alter the function of this zinc finger transcription factor and its role in causing this developmental anomaly.

Received for publication, February 18, 2004

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^b Both authors contributed equally to this work.

^c A Medical Research Council (MRC) Ph.D. student.

^d An MRC Clinical Training Fellow.

^o To whom correspondence should be addressed. Tel.: 44-1865-857-501; Fax: 44-1865-857-502; E-mail: rajesh.thakker{at}ndm.ox.ac.uk.

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