Human Molecular Genetics Advance Access published online on January 8, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddl454
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© The Author 2007. Published by Oxford University Press. All rights reserved
Functional Characterisation of GATA3 Mutations causing the Hypoparathyroidism-Deafness-Renal Dysplasia (HDR) Syndrome: insight into mechanisms of DNA binding by the GATA3 transcription factor.
1 Academic Endocrine Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Churchill Hospital, Headington, Oxford, OX3 7LJ, United Kingdom. 2 Department of Clinical Genetics, Centre for Human Genetics, University Hospital Leuven, Herestraat 49, B3000, Leuven, Belgium. 3 Royal Hospital for Sick Children, Dalnair St., Glasgow, G3 8SJ, United Kingdom. 4 Clinical and Molecular Genetics Unit, Institute for Child Health, London WC1N 1EH, United Kingdom. 5 University of Würtzburg, Department of Medicine, Endocrinology, Josef-Schneider-Str. 2, 97080 Würtzburg, Germany 6 Hopital Lenval, 57 Av. De la Californie, 06 200, Nice, France 7 Service de Gènètique Mèdicale, CHU la Milètrie, B.P. 577, 86021, Poitiers-Cedex, France 8 Royal Manchester Childrens Hospital, Hospital Rd., Pendlebury, Manchester, M27 4HA, United Kingdom 9 Department of Genetic Medicine, Women's and Children's Hospital, 72 King William Road, North Adelaide, SA 5006, Adelaide, Australia 10 Unidad de Genetica Medica, Hospital Universitario Virgen de la Arraxaca, Ctra Madrid-Cartagena, El Palmar, 30120, Spain 11 Hunter Genetics, PO Box 84, Waratah, New South Wales 2298, Australia 12 Children's Memorial Hospital, 2300 Children's Plaza, Chicago, Illinois 60614-3394, USA 13 Calcium Research Laboratory, Royal Victoria Hospital, 687 Pine Av. West, Montreal, Quebec, H3A 1A1, Canada 14 Department of Clinical Genetics, St. Mary's Hospital, Hathersage Road, Manchester M13 0JH, United Kingdom 15 Department of Paediatrics Medical University, Graz, Auenbruggerplatz 30, A-8036 Graz, Austria 16 Department of Paediatrics, Saint Mary's Hospital for Women and Children, Hathersage Rd, Manchester, M13 OJH, United Kingdom 17 Academic Nephrology Unit, Sheffield Kidney Institute, University of Sheffield, Northern General Hospital, Herries Road, Sheffield S5 7AU, United Kingdom. 18 Pediatric Nephrology Unit, Shaare Zedek Medical Centre, POB 3235, Jerusalem, Israel 19 Birmingham Children's Hospital, Steelhouse Lane, Birmingham, B4 6NH, United Kingdom 20 Department of Clinical Genetics, St.Michael's Hospital, Bristol, BS2 8EG, United Kingdom 21 Institute of Medical Genetics, Yorkhill NHS Trust, Dalnair St. Glasgow, G3 8SJ, United Kingdom 22 Pediatric Endocrine Unit, University Hospital, Lille, France
* Address for correspondence and reprints: Professor R.V. Thakker, MD, FRCP, FRCPath, FMed Sci. Academic Endocrine Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Churchill Hospital, Headington, Oxford, OX3 7LJ, UK Tel: 44-1865-857501; Fax: 44-1865-857502; email: rajesh.thakker{at}ndm.ox.ac.uk
Received October 18, 2006; Revised November 30, 2006; Accepted November 30, 2006
The hypoparathyroidism-deafness-renal dysplasia (HDR) syndrome is an autosomal dominant disorder caused by mutations of the dual zinc finger transcription factor, GATA3. We investigated 21 HDR probands and 14 patients with isolated hypoparathyroidism for GATA3 abnormalities. Thirteen different heterozygous germline mutations were identified in patients with HDR. These consisted of 3 nonsense mutations, 6 frameshifting deletions, 2 frameshifting insertions, one missense (Leu348Arg) mutation, and one acceptor splice site mutation. The splice site mutation was demonstrated to cause a pre-mRNA processing abnormality leading to the use of an alternative acceptor site 8-bp downstream of the normal site, resulting in a frameshift and prematurely terminated protein. Electrophoretic mobility shift assays (EMSAs) revealed three classes of GATA3 mutations: those that lead to a loss of DNA binding which represent over 90% of all mutations, and involved a loss of the carboxy-terminal zinc finger; those that resulted in a reduced DNA binding affinity; and those (e.g., Leu348Arg) that did not alter DNA binding or the affinity but likely altered the conformational change that occurs during binding in the DNA major groove as predicted by a three-dimensional modeling. These results elucidate further the molecular mechanisms underlying the altered functions of mutants of this zinc finger transcription factor and their role in causing this developmental anomaly. No mutations were identified in patients with isolated hypoparathyroidism, thereby indicating that GATA3 abnormalities are more likely to result in 2 or more of the phenotypic features of the HDR syndrome and not in one, such as isolated hypoparathyroidism.
The authors wish it to be known that, in their opinion, the first 3 authors should be regarded as joint first authors.
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