Human Molecular Genetics Advance Access originally published online on January 8, 2007
Human Molecular Genetics 2007 16(3):265-275; doi:10.1093/hmg/ddl454
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Functional characterization of GATA3 mutations causing the hypoparathyroidism-deafness-renal (HDR) dysplasia syndrome: insight into mechanisms of DNA binding by the GATA3 transcription factor
1 Academic Endocrine Unit, Nuffield Department of Clinical Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, Churchill Hospital, Headington, Oxford OX3 7LJ, UK, 2 Department of Clinical Genetics, Centre for Human Genetics, University Hospital Leuven, Herestraat 49, B3000 Leuven, Belgium, 3 Royal Hospital for Sick Children, Dalnair Street, Glasgow G3 8SJ, UK, 4 Clinical and Molecular Genetics Unit, Institute for Child Health, London WC1 N1EH, UK, 5 Department of Medicine, Endocrinology, University of Würtzburg, 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 Road, Pendlebury, Manchester M27 4HA, UK, 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, ILL 60614-3394, USA, 13 Calcium Research Laboratory, Royal Victoria Hospital, 687 Pine Av. West, Montreal, Quebec H3A 1A1, Canada, 14 Department of Clinical Genetics, 15 Department of Paediatrics, Saint Mary's Hospital for Women and Children, Hathersage Road, Manchester M13 OJH, UK, 16 Department of Paediatrics Medical University, Graz, Auenbruggerplatz 30, A-8036 Graz, Austria, 17 Academic Nephrology Unit, Sheffield Kidney Institute, University of Sheffield, Northern General Hospital, Herries Road, Sheffield S5 7AU, UK, 18 Pediatric Nephrology Unit, Shaare Zedek Medical Centre, POB 3235, Jerusalem, Israel, 19 Birmingham Children's Hospital, Steelhouse Lane, Birmingham B4 6NH, UK, 20 Department of Clinical Genetics, St Michael's Hospital, Bristol BS2 8EG, UK, 21 Institute of Medical Genetics, Yorkhill NHS Trust, Dalnair Street, Glasgow G3 8SJ, UK and 22 Pediatric Endocrine Unit, University Hospital, Lille, France
* To whom correspondence should be addressed. Tel: +44 1865857501; Fax: +44 1865857502; Email: rajesh.thakker{at}ndm.ox.ac.uk
Received October 18, 2006; Accepted November 30, 2006
The hypoparathyroidism-deafness-renal (HDR) dysplasia 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 three nonsense mutations, six frameshifting deletions, two 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 two 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 three authors should be regarded as joint First Authors.
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