dc.contributor.author | Shaw-Smith, C | |
dc.contributor.author | De Franco, E | |
dc.contributor.author | Lango Allen, H | |
dc.contributor.author | Batlle, M | |
dc.contributor.author | Flanagan, SE | |
dc.contributor.author | Borowiec, M | |
dc.contributor.author | Taplin, CE | |
dc.contributor.author | van Alfen-van der Velden, J | |
dc.contributor.author | Cruz-Rojo, J | |
dc.contributor.author | Perez de Nanclares, G | |
dc.contributor.author | Miedzybrodzka, Z | |
dc.contributor.author | Deja, G | |
dc.contributor.author | Wlodarska, I | |
dc.contributor.author | Mlynarski, W | |
dc.contributor.author | Ferrer, J | |
dc.contributor.author | Hattersley, AT | |
dc.contributor.author | Ellard, S | |
dc.date.accessioned | 2016-03-18T10:47:29Z | |
dc.date.issued | 2014-04-02 | |
dc.description.abstract | The GATA family zinc finger transcription factors GATA4 and GATA6 are known to play important roles in the development of the pancreas. In mice, both Gata4 and Gata6 are required for pancreatic development. In humans, GATA6 haploinsufficiency can cause pancreatic agenesis and heart defects. Congenital heart defects also are common in patients with GATA4 mutations and deletions, but the role of GATA4 in the developing human pancreas is unproven. We report five patients with deletions (n = 4) or mutations of the GATA4 gene who have diabetes and a variable exocrine phenotype. In four cases, diabetes presented in the neonatal period (age at diagnosis 1-7 days). A de novo GATA4 missense mutation (p.N273K) was identified in a patient with complete absence of the pancreas confirmed at postmortem. This mutation affects a highly conserved residue located in the second zinc finger domain of the GATA4 protein. In vitro studies showed reduced DNA binding and transactivational activity of the mutant protein. We show that GATA4 mutations/deletions are a cause of neonatal or childhood-onset diabetes with or without exocrine insufficiency. These results confirm a role for GATA4 in normal development of the human pancreas. | en_GB |
dc.description.sponsorship | The research leading to these results received funding from the European Community’s 7th Framework Programme (FP7/2007-2013) under grant agreement number FP7-PEOPLE-ITN-2008 (Marie Curie Initial Training Network, Biology of Liver and Pancreatic Development and Disease) and grant agreement number 223211 (Collaborative European Effort to Develop Diabetes Diagnostics), Ministerio de Economía y Competitividad (SAF2011-27086), Diabetes UK (ref. 11/0004193), and the Wellcome Trust. S.E. and A.T.H. are employed as core members of staff within the National Institute for Health Research–funded Exeter Clinical Research Facility. S.E., J.F., and A.T.H. are Wellcome Trust Senior Investigators and A.T.H. is a National Institute for Health Research Senior Investigator. M.B. and W.M. are supported by National Science Center, Poland (NCN) grant 2011/01/M/NZ5/02815 and by Innovative Economy Operational Programme–Activity 1.2 (the TEAM Programme coordinated by the Foundation for Polish Science). | en_GB |
dc.identifier.citation | Vol. 63 (8), pp. 2888 - 2894 | en_GB |
dc.identifier.doi | 10.2337/db14-0061 | |
dc.identifier.other | db14-0061 | |
dc.identifier.uri | http://hdl.handle.net/10871/20751 | |
dc.language.iso | en | en_GB |
dc.publisher | American Diabetes Association | en_GB |
dc.relation.url | http://www.ncbi.nlm.nih.gov/pubmed/24696446 | en_GB |
dc.rights | © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. | en_GB |
dc.subject | Amino Acid Sequence | en_GB |
dc.subject | DNA | en_GB |
dc.subject | Diabetes Mellitus | en_GB |
dc.subject | GATA4 Transcription Factor | en_GB |
dc.subject | Genetic Predisposition to Disease | en_GB |
dc.subject | Humans | en_GB |
dc.subject | Infant, Newborn | en_GB |
dc.subject | Molecular Sequence Data | en_GB |
dc.subject | Mutation | en_GB |
dc.subject | Pancreas | en_GB |
dc.subject | Receptors, Fc | en_GB |
dc.title | GATA4 mutations are a cause of neonatal and childhood-onset diabetes | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2016-03-18T10:47:29Z | |
exeter.place-of-publication | United States | |
dc.description | This is the author accepted manuscript. The final version is available from the American Diabetes Association via the DOI in this record. | en_GB |
dc.identifier.journal | Diabetes | en_GB |