Functional characterization of GATA3 mutations causing the hypoparathyroidism-deafness-renal (HDR) dysplasia syndrome : Insight into mechanisms of DNA binding by the GATA3 transcription factor
Identifieur interne : 009F92 ( Main/Merge ); précédent : 009F91; suivant : 009F93Functional characterization of GATA3 mutations causing the hypoparathyroidism-deafness-renal (HDR) dysplasia syndrome : Insight into mechanisms of DNA binding by the GATA3 transcription factor
Auteurs : Asif Ali [Royaume-Uni] ; Paul T. Christie [Royaume-Uni] ; Irina V. Grigorieva [Royaume-Uni] ; Brian Harding [Royaume-Uni] ; Hilde Van Esch [Belgique] ; S. Faisal Ahmed [Royaume-Uni] ; Maria Bitner-Glindzicz [Royaume-Uni] ; Eberhard Blind [Allemagne] ; Catherine Bloch [France] ; Patricia Christin [France] ; Peter Clayton [Royaume-Uni] ; Jozef Gecz [Australie] ; Brigitte Gilbert-Dussardier [France] ; Encarna Guillen-Navarro [Espagne] ; Anna Hackett [Australie] ; Isil Halac ; Geoffrey N. Hendy ; Fiona Lalloo ; Christoph J. Mache ; Zulf Mughal ; Albert C. M. Ong ; Choni Rinat ; Nicholas Shaw ; Sarah F. Smithson ; John Tolmie ; Jacques Weill ; M. Andrew Nesbit [Royaume-Uni] ; Rajesh V. Thakker [Royaume-Uni]Source :
- Human molecular genetics : (Print) [ 0964-6906 ] ; 2007.
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- topic : Génétique.
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Abstract
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 frame-shift 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.
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Christie</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Academic Endocrine Unit, Nuffield Department of Clinical Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, Churchill Hospital</s1><s2>Headington, Oxford OX3 7LJ</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>27 aut.</sZ><sZ>28 aut.</sZ></inist:fA14><country>Royaume-Uni</country><wicri:noRegion>Headington, Oxford OX3 7LJ</wicri:noRegion><orgName type="university">Université d'Oxford</orgName><placeName><settlement type="city">Oxford</settlement><region type="nation">Angleterre</region><region type="région" nuts="1">Oxfordshire</region></placeName></affiliation></author><author><name sortKey="Grigorieva, Irina V" sort="Grigorieva, Irina V" uniqKey="Grigorieva I" first="Irina V." last="Grigorieva">Irina V. 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Faisal Ahmed</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Royal Hospital for Sick Children, Dalnair Street</s1><s2>Glasgow G3 8SJ</s2><s3>GBR</s3><sZ>6 aut.</sZ></inist:fA14><country>Royaume-Uni</country><wicri:noRegion>Glasgow G3 8SJ</wicri:noRegion></affiliation></author><author><name sortKey="Bitner Glindzicz, Maria" sort="Bitner Glindzicz, Maria" uniqKey="Bitner Glindzicz M" first="Maria" last="Bitner-Glindzicz">Maria Bitner-Glindzicz</name><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Clinical and Molecular Genetics Unit, Institute for Child Health</s1><s2>London WC1 N1EH</s2><s3>GBR</s3><sZ>7 aut.</sZ></inist:fA14><country>Royaume-Uni</country><wicri:noRegion>London WC1 N1EH</wicri:noRegion></affiliation></author><author><name sortKey="Blind, Eberhard" sort="Blind, Eberhard" uniqKey="Blind E" first="Eberhard" last="Blind">Eberhard Blind</name><affiliation wicri:level="3"><inist:fA14 i1="05"><s1>Department of Medicine, Endocrinology, University of Würtzburg, Josef-Schneider-Str. 2</s1><s2>97080 Würtzburg</s2><s3>DEU</s3><sZ>8 aut.</sZ></inist:fA14><country>Allemagne</country><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Basse-Franconie</region><settlement type="city">Wurtzbourg</settlement></placeName></affiliation></author><author><name sortKey="Bloch, Catherine" sort="Bloch, Catherine" uniqKey="Bloch C" first="Catherine" last="Bloch">Catherine Bloch</name><affiliation wicri:level="3"><inist:fA14 i1="06"><s1>Hopital Lenval, 57 Av. De la Californie 06 200</s1><s2>Nice</s2><s3>FRA</s3><sZ>9 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Provence-Alpes-Côte d'Azur</region><region type="old region">Provence-Alpes-Côte d'Azur</region><settlement type="city">Nice</settlement></placeName></affiliation></author><author><name sortKey="Christin, Patricia" sort="Christin, Patricia" uniqKey="Christin P" first="Patricia" last="Christin">Patricia Christin</name><affiliation wicri:level="1"><inist:fA14 i1="07"><s1>Service de Gènètique Mèdicale, CHU la Milètrie, B.P. 577</s1><s2>86021 Poitiers</s2><s3>FRA</s3><sZ>10 aut.</sZ><sZ>13 aut.</sZ></inist:fA14><country>France</country><wicri:noRegion>86021 Poitiers</wicri:noRegion><wicri:noRegion>B.P. 577</wicri:noRegion><wicri:noRegion>86021 Poitiers</wicri:noRegion></affiliation></author><author><name sortKey="Clayton, Peter" sort="Clayton, Peter" uniqKey="Clayton P" first="Peter" last="Clayton">Peter Clayton</name><affiliation wicri:level="1"><inist:fA14 i1="08"><s1>Royal Manchester Childrens Hospital, Hospital Road, Pendlebury</s1><s2>Manchester M27 4HA</s2><s3>GBR</s3><sZ>11 aut.</sZ></inist:fA14><country>Royaume-Uni</country><wicri:noRegion>Manchester M27 4HA</wicri:noRegion></affiliation></author><author><name sortKey="Gecz, Jozef" sort="Gecz, Jozef" uniqKey="Gecz J" first="Jozef" last="Gecz">Jozef Gecz</name><affiliation wicri:level="1"><inist:fA14 i1="09"><s1>Department of Genetic Medicine, Women's and Children's Hospital, 72 King William Road, North Adelaide</s1><s2>SA 5006, Adelaide</s2><s3>AUS</s3><sZ>12 aut.</sZ></inist:fA14><country>Australie</country><wicri:noRegion>SA 5006, Adelaide</wicri:noRegion></affiliation></author><author><name sortKey="Gilbert Dussardier, Brigitte" sort="Gilbert Dussardier, Brigitte" uniqKey="Gilbert Dussardier B" first="Brigitte" last="Gilbert-Dussardier">Brigitte Gilbert-Dussardier</name><affiliation wicri:level="1"><inist:fA14 i1="07"><s1>Service de Gènètique Mèdicale, CHU la Milètrie, B.P. 577</s1><s2>86021 Poitiers</s2><s3>FRA</s3><sZ>10 aut.</sZ><sZ>13 aut.</sZ></inist:fA14><country>France</country><wicri:noRegion>86021 Poitiers</wicri:noRegion><wicri:noRegion>B.P. 577</wicri:noRegion><wicri:noRegion>86021 Poitiers</wicri:noRegion></affiliation></author><author><name sortKey="Guillen Navarro, Encarna" sort="Guillen Navarro, Encarna" uniqKey="Guillen Navarro E" first="Encarna" last="Guillen-Navarro">Encarna Guillen-Navarro</name><affiliation wicri:level="2"><inist:fA14 i1="10"><s1>Unidad de Genetica Medica, Hospital Universitario Virgen de la Arraxaca, Ctra Madrid-Cartagena</s1><s2>El Palmar 30120</s2><s3>ESP</s3><sZ>14 aut.</sZ></inist:fA14><country>Espagne</country><placeName><region nuts="2" type="communauté">Région de Murcie</region></placeName></affiliation></author><author><name sortKey="Hackett, Anna" sort="Hackett, Anna" uniqKey="Hackett A" first="Anna" last="Hackett">Anna Hackett</name><affiliation wicri:level="1"><inist:fA14 i1="11"><s1>Hunter Genetics, PO Box 84</s1><s2>Waratah, New South Wales 2298</s2><s3>AUS</s3><sZ>15 aut.</sZ></inist:fA14><country>Australie</country><wicri:noRegion>Waratah, New South Wales 2298</wicri:noRegion></affiliation></author><author><name sortKey="Halac, Isil" sort="Halac, Isil" uniqKey="Halac I" first="Isil" last="Halac">Isil Halac</name></author><author><name sortKey="Hendy, Geoffrey N" sort="Hendy, Geoffrey N" uniqKey="Hendy G" first="Geoffrey N." last="Hendy">Geoffrey N. Hendy</name></author><author><name sortKey="Lalloo, Fiona" sort="Lalloo, Fiona" uniqKey="Lalloo F" first="Fiona" last="Lalloo">Fiona Lalloo</name></author><author><name sortKey="Mache, Christoph J" sort="Mache, Christoph J" uniqKey="Mache C" first="Christoph J." last="Mache">Christoph J. Mache</name></author><author><name sortKey="Mughal, Zulf" sort="Mughal, Zulf" uniqKey="Mughal Z" first="Zulf" last="Mughal">Zulf Mughal</name></author><author><name sortKey="Ong, Albert C M" sort="Ong, Albert C M" uniqKey="Ong A" first="Albert C. M." last="Ong">Albert C. M. Ong</name></author><author><name sortKey="Rinat, Choni" sort="Rinat, Choni" uniqKey="Rinat C" first="Choni" last="Rinat">Choni Rinat</name></author><author><name sortKey="Shaw, Nicholas" sort="Shaw, Nicholas" uniqKey="Shaw N" first="Nicholas" last="Shaw">Nicholas Shaw</name></author><author><name sortKey="Smithson, Sarah F" sort="Smithson, Sarah F" uniqKey="Smithson S" first="Sarah F." last="Smithson">Sarah F. Smithson</name></author><author><name sortKey="Tolmie, John" sort="Tolmie, John" uniqKey="Tolmie J" first="John" last="Tolmie">John Tolmie</name></author><author><name sortKey="Weill, Jacques" sort="Weill, Jacques" uniqKey="Weill J" first="Jacques" last="Weill">Jacques Weill</name></author><author><name sortKey="Nesbit, M Andrew" sort="Nesbit, M Andrew" uniqKey="Nesbit M" first="M. Andrew" last="Nesbit">M. Andrew Nesbit</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Academic Endocrine Unit, Nuffield Department of Clinical Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, Churchill Hospital</s1><s2>Headington, Oxford OX3 7LJ</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>27 aut.</sZ><sZ>28 aut.</sZ></inist:fA14><country>Royaume-Uni</country><wicri:noRegion>Headington, Oxford OX3 7LJ</wicri:noRegion><orgName type="university">Université d'Oxford</orgName><placeName><settlement type="city">Oxford</settlement><region type="nation">Angleterre</region><region type="région" nuts="1">Oxfordshire</region></placeName></affiliation></author><author><name sortKey="Thakker, Rajesh V" sort="Thakker, Rajesh V" uniqKey="Thakker R" first="Rajesh V." last="Thakker">Rajesh V. Thakker</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Academic Endocrine Unit, Nuffield Department of Clinical Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, Churchill Hospital</s1><s2>Headington, Oxford OX3 7LJ</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>27 aut.</sZ><sZ>28 aut.</sZ></inist:fA14><country>Royaume-Uni</country><wicri:noRegion>Headington, Oxford OX3 7LJ</wicri:noRegion><orgName type="university">Université d'Oxford</orgName><placeName><settlement type="city">Oxford</settlement><region type="nation">Angleterre</region><region type="région" nuts="1">Oxfordshire</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">INIST</idno><idno type="inist">07-0187922</idno><date when="2007">2007</date><idno type="stanalyst">PASCAL 07-0187922 INIST</idno><idno type="RBID">Pascal:07-0187922</idno><idno type="wicri:Area/PascalFrancis/Corpus">003D06</idno><idno type="wicri:Area/PascalFrancis/Curation">002382</idno><idno type="wicri:Area/PascalFrancis/Checkpoint">003880</idno><idno type="wicri:explorRef" wicri:stream="PascalFrancis" wicri:step="Checkpoint">003880</idno><idno type="wicri:doubleKey">0964-6906:2007:Ali A:functional:characterization:of</idno><idno type="wicri:Area/Main/Merge">009F92</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">Functional characterization of GATA3 mutations causing the hypoparathyroidism-deafness-renal (HDR) dysplasia syndrome : Insight into mechanisms of DNA binding by the GATA3 transcription factor</title><author><name sortKey="Ali, Asif" sort="Ali, Asif" uniqKey="Ali A" first="Asif" last="Ali">Asif Ali</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Academic Endocrine Unit, Nuffield Department of Clinical Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, Churchill Hospital</s1><s2>Headington, Oxford OX3 7LJ</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>27 aut.</sZ><sZ>28 aut.</sZ></inist:fA14><country>Royaume-Uni</country><wicri:noRegion>Headington, Oxford OX3 7LJ</wicri:noRegion><orgName type="university">Université d'Oxford</orgName><placeName><settlement type="city">Oxford</settlement><region type="nation">Angleterre</region><region type="région" nuts="1">Oxfordshire</region></placeName></affiliation></author><author><name sortKey="Christie, Paul T" sort="Christie, Paul T" uniqKey="Christie P" first="Paul T." last="Christie">Paul T. Christie</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Academic Endocrine Unit, Nuffield Department of Clinical Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, Churchill Hospital</s1><s2>Headington, Oxford OX3 7LJ</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>27 aut.</sZ><sZ>28 aut.</sZ></inist:fA14><country>Royaume-Uni</country><wicri:noRegion>Headington, Oxford OX3 7LJ</wicri:noRegion><orgName type="university">Université d'Oxford</orgName><placeName><settlement type="city">Oxford</settlement><region type="nation">Angleterre</region><region type="région" nuts="1">Oxfordshire</region></placeName></affiliation></author><author><name sortKey="Grigorieva, Irina V" sort="Grigorieva, Irina V" uniqKey="Grigorieva I" first="Irina V." last="Grigorieva">Irina V. Grigorieva</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Academic Endocrine Unit, Nuffield Department of Clinical Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, Churchill Hospital</s1><s2>Headington, Oxford OX3 7LJ</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>27 aut.</sZ><sZ>28 aut.</sZ></inist:fA14><country>Royaume-Uni</country><wicri:noRegion>Headington, Oxford OX3 7LJ</wicri:noRegion><orgName type="university">Université d'Oxford</orgName><placeName><settlement type="city">Oxford</settlement><region type="nation">Angleterre</region><region type="région" nuts="1">Oxfordshire</region></placeName></affiliation></author><author><name sortKey="Harding, Brian" sort="Harding, Brian" uniqKey="Harding B" first="Brian" last="Harding">Brian Harding</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Academic Endocrine Unit, Nuffield Department of Clinical Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, Churchill Hospital</s1><s2>Headington, Oxford OX3 7LJ</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>27 aut.</sZ><sZ>28 aut.</sZ></inist:fA14><country>Royaume-Uni</country><wicri:noRegion>Headington, Oxford OX3 7LJ</wicri:noRegion><orgName type="university">Université d'Oxford</orgName><placeName><settlement type="city">Oxford</settlement><region type="nation">Angleterre</region><region type="région" nuts="1">Oxfordshire</region></placeName></affiliation></author><author><name sortKey="Van Esch, Hilde" sort="Van Esch, Hilde" uniqKey="Van Esch H" first="Hilde" last="Van Esch">Hilde Van Esch</name><affiliation wicri:level="3"><inist:fA14 i1="02"><s1>Department of Clinical Genetics, Centre for Human Genetics, University Hospital Leuven, Herestraat 49</s1><s2>3000 Leuven</s2><s3>BEL</s3><sZ>5 aut.</sZ></inist:fA14><country>Belgique</country><placeName><region type="province" nuts="2">Province du Brabant flamand</region><settlement type="city">Louvain</settlement></placeName></affiliation></author><author><name sortKey="Faisal Ahmed, S" sort="Faisal Ahmed, S" uniqKey="Faisal Ahmed S" first="S." last="Faisal Ahmed">S. Faisal Ahmed</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Royal Hospital for Sick Children, Dalnair Street</s1><s2>Glasgow G3 8SJ</s2><s3>GBR</s3><sZ>6 aut.</sZ></inist:fA14><country>Royaume-Uni</country><wicri:noRegion>Glasgow G3 8SJ</wicri:noRegion></affiliation></author><author><name sortKey="Bitner Glindzicz, Maria" sort="Bitner Glindzicz, Maria" uniqKey="Bitner Glindzicz M" first="Maria" last="Bitner-Glindzicz">Maria Bitner-Glindzicz</name><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Clinical and Molecular Genetics Unit, Institute for Child Health</s1><s2>London WC1 N1EH</s2><s3>GBR</s3><sZ>7 aut.</sZ></inist:fA14><country>Royaume-Uni</country><wicri:noRegion>London WC1 N1EH</wicri:noRegion></affiliation></author><author><name sortKey="Blind, Eberhard" sort="Blind, Eberhard" uniqKey="Blind E" first="Eberhard" last="Blind">Eberhard Blind</name><affiliation wicri:level="3"><inist:fA14 i1="05"><s1>Department of Medicine, Endocrinology, University of Würtzburg, Josef-Schneider-Str. 2</s1><s2>97080 Würtzburg</s2><s3>DEU</s3><sZ>8 aut.</sZ></inist:fA14><country>Allemagne</country><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Basse-Franconie</region><settlement type="city">Wurtzbourg</settlement></placeName></affiliation></author><author><name sortKey="Bloch, Catherine" sort="Bloch, Catherine" uniqKey="Bloch C" first="Catherine" last="Bloch">Catherine Bloch</name><affiliation wicri:level="3"><inist:fA14 i1="06"><s1>Hopital Lenval, 57 Av. De la Californie 06 200</s1><s2>Nice</s2><s3>FRA</s3><sZ>9 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Provence-Alpes-Côte d'Azur</region><region type="old region">Provence-Alpes-Côte d'Azur</region><settlement type="city">Nice</settlement></placeName></affiliation></author><author><name sortKey="Christin, Patricia" sort="Christin, Patricia" uniqKey="Christin P" first="Patricia" last="Christin">Patricia Christin</name><affiliation wicri:level="1"><inist:fA14 i1="07"><s1>Service de Gènètique Mèdicale, CHU la Milètrie, B.P. 577</s1><s2>86021 Poitiers</s2><s3>FRA</s3><sZ>10 aut.</sZ><sZ>13 aut.</sZ></inist:fA14><country>France</country><wicri:noRegion>86021 Poitiers</wicri:noRegion><wicri:noRegion>B.P. 577</wicri:noRegion><wicri:noRegion>86021 Poitiers</wicri:noRegion></affiliation></author><author><name sortKey="Clayton, Peter" sort="Clayton, Peter" uniqKey="Clayton P" first="Peter" last="Clayton">Peter Clayton</name><affiliation wicri:level="1"><inist:fA14 i1="08"><s1>Royal Manchester Childrens Hospital, Hospital Road, Pendlebury</s1><s2>Manchester M27 4HA</s2><s3>GBR</s3><sZ>11 aut.</sZ></inist:fA14><country>Royaume-Uni</country><wicri:noRegion>Manchester M27 4HA</wicri:noRegion></affiliation></author><author><name sortKey="Gecz, Jozef" sort="Gecz, Jozef" uniqKey="Gecz J" first="Jozef" last="Gecz">Jozef Gecz</name><affiliation wicri:level="1"><inist:fA14 i1="09"><s1>Department of Genetic Medicine, Women's and Children's Hospital, 72 King William Road, North Adelaide</s1><s2>SA 5006, Adelaide</s2><s3>AUS</s3><sZ>12 aut.</sZ></inist:fA14><country>Australie</country><wicri:noRegion>SA 5006, Adelaide</wicri:noRegion></affiliation></author><author><name sortKey="Gilbert Dussardier, Brigitte" sort="Gilbert Dussardier, Brigitte" uniqKey="Gilbert Dussardier B" first="Brigitte" last="Gilbert-Dussardier">Brigitte Gilbert-Dussardier</name><affiliation wicri:level="1"><inist:fA14 i1="07"><s1>Service de Gènètique Mèdicale, CHU la Milètrie, B.P. 577</s1><s2>86021 Poitiers</s2><s3>FRA</s3><sZ>10 aut.</sZ><sZ>13 aut.</sZ></inist:fA14><country>France</country><wicri:noRegion>86021 Poitiers</wicri:noRegion><wicri:noRegion>B.P. 577</wicri:noRegion><wicri:noRegion>86021 Poitiers</wicri:noRegion></affiliation></author><author><name sortKey="Guillen Navarro, Encarna" sort="Guillen Navarro, Encarna" uniqKey="Guillen Navarro E" first="Encarna" last="Guillen-Navarro">Encarna Guillen-Navarro</name><affiliation wicri:level="2"><inist:fA14 i1="10"><s1>Unidad de Genetica Medica, Hospital Universitario Virgen de la Arraxaca, Ctra Madrid-Cartagena</s1><s2>El Palmar 30120</s2><s3>ESP</s3><sZ>14 aut.</sZ></inist:fA14><country>Espagne</country><placeName><region nuts="2" type="communauté">Région de Murcie</region></placeName></affiliation></author><author><name sortKey="Hackett, Anna" sort="Hackett, Anna" uniqKey="Hackett A" first="Anna" last="Hackett">Anna Hackett</name><affiliation wicri:level="1"><inist:fA14 i1="11"><s1>Hunter Genetics, PO Box 84</s1><s2>Waratah, New South Wales 2298</s2><s3>AUS</s3><sZ>15 aut.</sZ></inist:fA14><country>Australie</country><wicri:noRegion>Waratah, New South Wales 2298</wicri:noRegion></affiliation></author><author><name sortKey="Halac, Isil" sort="Halac, Isil" uniqKey="Halac I" first="Isil" last="Halac">Isil Halac</name></author><author><name sortKey="Hendy, Geoffrey N" sort="Hendy, Geoffrey N" uniqKey="Hendy G" first="Geoffrey N." last="Hendy">Geoffrey N. Hendy</name></author><author><name sortKey="Lalloo, Fiona" sort="Lalloo, Fiona" uniqKey="Lalloo F" first="Fiona" last="Lalloo">Fiona Lalloo</name></author><author><name sortKey="Mache, Christoph J" sort="Mache, Christoph J" uniqKey="Mache C" first="Christoph J." last="Mache">Christoph J. Mache</name></author><author><name sortKey="Mughal, Zulf" sort="Mughal, Zulf" uniqKey="Mughal Z" first="Zulf" last="Mughal">Zulf Mughal</name></author><author><name sortKey="Ong, Albert C M" sort="Ong, Albert C M" uniqKey="Ong A" first="Albert C. M." last="Ong">Albert C. M. Ong</name></author><author><name sortKey="Rinat, Choni" sort="Rinat, Choni" uniqKey="Rinat C" first="Choni" last="Rinat">Choni Rinat</name></author><author><name sortKey="Shaw, Nicholas" sort="Shaw, Nicholas" uniqKey="Shaw N" first="Nicholas" last="Shaw">Nicholas Shaw</name></author><author><name sortKey="Smithson, Sarah F" sort="Smithson, Sarah F" uniqKey="Smithson S" first="Sarah F." last="Smithson">Sarah F. Smithson</name></author><author><name sortKey="Tolmie, John" sort="Tolmie, John" uniqKey="Tolmie J" first="John" last="Tolmie">John Tolmie</name></author><author><name sortKey="Weill, Jacques" sort="Weill, Jacques" uniqKey="Weill J" first="Jacques" last="Weill">Jacques Weill</name></author><author><name sortKey="Nesbit, M Andrew" sort="Nesbit, M Andrew" uniqKey="Nesbit M" first="M. Andrew" last="Nesbit">M. Andrew Nesbit</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Academic Endocrine Unit, Nuffield Department of Clinical Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, Churchill Hospital</s1><s2>Headington, Oxford OX3 7LJ</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>27 aut.</sZ><sZ>28 aut.</sZ></inist:fA14><country>Royaume-Uni</country><wicri:noRegion>Headington, Oxford OX3 7LJ</wicri:noRegion><orgName type="university">Université d'Oxford</orgName><placeName><settlement type="city">Oxford</settlement><region type="nation">Angleterre</region><region type="région" nuts="1">Oxfordshire</region></placeName></affiliation></author><author><name sortKey="Thakker, Rajesh V" sort="Thakker, Rajesh V" uniqKey="Thakker R" first="Rajesh V." last="Thakker">Rajesh V. Thakker</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Academic Endocrine Unit, Nuffield Department of Clinical Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, Churchill Hospital</s1><s2>Headington, Oxford OX3 7LJ</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>27 aut.</sZ><sZ>28 aut.</sZ></inist:fA14><country>Royaume-Uni</country><wicri:noRegion>Headington, Oxford OX3 7LJ</wicri:noRegion><orgName type="university">Université d'Oxford</orgName><placeName><settlement type="city">Oxford</settlement><region type="nation">Angleterre</region><region type="région" nuts="1">Oxfordshire</region></placeName></affiliation></author></analytic><series><title level="j" type="main">Human molecular genetics : (Print)</title><title level="j" type="abbreviated">Hum. mol. genet. : (Print)</title><idno type="ISSN">0964-6906</idno><imprint><date when="2007">2007</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Human molecular genetics : (Print)</title><title level="j" type="abbreviated">Hum. mol. genet. : (Print)</title><idno type="ISSN">0964-6906</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Characterization</term><term>DNA</term><term>Genetics</term><term>Hearing loss</term><term>Hypoparathyroidism</term><term>Mechanism</term><term>Mutation</term><term>Renal dysplasia</term><term>Syndrome</term><term>Transcription factor</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Caractérisation</term><term>Mutation</term><term>Dysplasie rénale</term><term>Syndrome</term><term>Mécanisme</term><term>DNA</term><term>Facteur transcription</term><term>Génétique</term><term>Hypoparathyroïdie</term><term>Surdité</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Génétique</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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 frame-shift 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.</div></front></TEI><affiliations><list><country><li>Allemagne</li><li>Australie</li><li>Belgique</li><li>Espagne</li><li>France</li><li>Royaume-Uni</li></country><region><li>Angleterre</li><li>Bavière</li><li>District de Basse-Franconie</li><li>Oxfordshire</li><li>Provence-Alpes-Côte d'Azur</li><li>Province du Brabant flamand</li><li>Région de Murcie</li></region><settlement><li>Louvain</li><li>Nice</li><li>Oxford</li><li>Wurtzbourg</li></settlement><orgName><li>Université d'Oxford</li></orgName></list><tree><noCountry><name sortKey="Halac, Isil" sort="Halac, Isil" uniqKey="Halac I" first="Isil" last="Halac">Isil Halac</name><name sortKey="Hendy, Geoffrey N" sort="Hendy, Geoffrey N" uniqKey="Hendy G" first="Geoffrey N." last="Hendy">Geoffrey N. Hendy</name><name sortKey="Lalloo, Fiona" sort="Lalloo, Fiona" uniqKey="Lalloo F" first="Fiona" last="Lalloo">Fiona Lalloo</name><name sortKey="Mache, Christoph J" sort="Mache, Christoph J" uniqKey="Mache C" first="Christoph J." last="Mache">Christoph J. Mache</name><name sortKey="Mughal, Zulf" sort="Mughal, Zulf" uniqKey="Mughal Z" first="Zulf" last="Mughal">Zulf Mughal</name><name sortKey="Ong, Albert C M" sort="Ong, Albert C M" uniqKey="Ong A" first="Albert C. M." last="Ong">Albert C. M. Ong</name><name sortKey="Rinat, Choni" sort="Rinat, Choni" uniqKey="Rinat C" first="Choni" last="Rinat">Choni Rinat</name><name sortKey="Shaw, Nicholas" sort="Shaw, Nicholas" uniqKey="Shaw N" first="Nicholas" last="Shaw">Nicholas Shaw</name><name sortKey="Smithson, Sarah F" sort="Smithson, Sarah F" uniqKey="Smithson S" first="Sarah F." last="Smithson">Sarah F. Smithson</name><name sortKey="Tolmie, John" sort="Tolmie, John" uniqKey="Tolmie J" first="John" last="Tolmie">John Tolmie</name><name sortKey="Weill, Jacques" sort="Weill, Jacques" uniqKey="Weill J" first="Jacques" last="Weill">Jacques Weill</name></noCountry><country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Ali, Asif" sort="Ali, Asif" uniqKey="Ali A" first="Asif" last="Ali">Asif Ali</name></region><name sortKey="Bitner Glindzicz, Maria" sort="Bitner Glindzicz, Maria" uniqKey="Bitner Glindzicz M" first="Maria" last="Bitner-Glindzicz">Maria Bitner-Glindzicz</name><name sortKey="Christie, Paul T" sort="Christie, Paul T" uniqKey="Christie P" first="Paul T." last="Christie">Paul T. Christie</name><name sortKey="Clayton, Peter" sort="Clayton, Peter" uniqKey="Clayton P" first="Peter" last="Clayton">Peter Clayton</name><name sortKey="Faisal Ahmed, S" sort="Faisal Ahmed, S" uniqKey="Faisal Ahmed S" first="S." last="Faisal Ahmed">S. Faisal Ahmed</name><name sortKey="Grigorieva, Irina V" sort="Grigorieva, Irina V" uniqKey="Grigorieva I" first="Irina V." last="Grigorieva">Irina V. Grigorieva</name><name sortKey="Harding, Brian" sort="Harding, Brian" uniqKey="Harding B" first="Brian" last="Harding">Brian Harding</name><name sortKey="Nesbit, M Andrew" sort="Nesbit, M Andrew" uniqKey="Nesbit M" first="M. Andrew" last="Nesbit">M. Andrew Nesbit</name><name sortKey="Thakker, Rajesh V" sort="Thakker, Rajesh V" uniqKey="Thakker R" first="Rajesh V." last="Thakker">Rajesh V. Thakker</name></country><country name="Belgique"><region name="Province du Brabant flamand"><name sortKey="Van Esch, Hilde" sort="Van Esch, Hilde" uniqKey="Van Esch H" first="Hilde" last="Van Esch">Hilde Van Esch</name></region></country><country name="Allemagne"><region name="Bavière"><name sortKey="Blind, Eberhard" sort="Blind, Eberhard" uniqKey="Blind E" first="Eberhard" last="Blind">Eberhard Blind</name></region></country><country name="France"><region name="Provence-Alpes-Côte d'Azur"><name sortKey="Bloch, Catherine" sort="Bloch, Catherine" uniqKey="Bloch C" first="Catherine" last="Bloch">Catherine Bloch</name></region><name sortKey="Christin, Patricia" sort="Christin, Patricia" uniqKey="Christin P" first="Patricia" last="Christin">Patricia Christin</name><name sortKey="Gilbert Dussardier, Brigitte" sort="Gilbert Dussardier, Brigitte" uniqKey="Gilbert Dussardier B" first="Brigitte" last="Gilbert-Dussardier">Brigitte Gilbert-Dussardier</name></country><country name="Australie"><noRegion><name sortKey="Gecz, Jozef" sort="Gecz, Jozef" uniqKey="Gecz J" first="Jozef" last="Gecz">Jozef Gecz</name></noRegion><name sortKey="Hackett, Anna" sort="Hackett, Anna" uniqKey="Hackett A" first="Anna" last="Hackett">Anna Hackett</name></country><country name="Espagne"><region name="Région de Murcie"><name sortKey="Guillen Navarro, Encarna" sort="Guillen Navarro, Encarna" uniqKey="Guillen Navarro E" first="Encarna" last="Guillen-Navarro">Encarna Guillen-Navarro</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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