GATA4 mutations are a cause of neonatal and childhood-onset diabetes.
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.
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K.
Charles
C
Shaw-Smith
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K.
Elisa
E
De Franco
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K.
Hana
H
Lango Allen
Genomic Programming of Beta-Cells Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, SpainCIBER de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona, Spain.
Marta
M
Batlle
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K.
Sarah E
SE
Flanagan
Department of Paediatrics, Oncology, Haematology and Diabetology, Medical University of Lodz, Lodz, Poland.
Maciej
M
Borowiec
Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA.
Craig E
CE
Taplin
Department of Pediatrics, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
Janiëlle
J
van Alfen-van der Velden
Unidad de Endocrinología Pediátrica Hospital, Universitario Doce de Octubre, Madrid, Spain.
Jaime
J
Cruz-Rojo
Molecular (Epi)Genetics Laboratory, Hospital Universitario Araba-Txagorritxu, BioAraba, Vitoria-Gasteiz, Spain.
Guiomar
G
Perez de Nanclares
Division of Applied Medicine, University of Aberdeen, Aberdeen, U.K.
Zosia
Z
Miedzybrodzka
Department of Paediatrics, Paediatric Endocrinology and Diabetes, Silesian Medical University, Katowice, Poland.
Grazyna
G
Deja
Center for Human Genetics, KU Leuven, Leuven, Belgium.
Iwona
I
Wlodarska
Department of Paediatrics, Oncology, Haematology and Diabetology, Medical University of Lodz, Lodz, Poland.
Wojciech
W
Mlynarski
Genomic Programming of Beta-Cells Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, SpainCIBER de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona, SpainDepartment of Medicine, Imperial College London, London, U.K.
Jorge
J
Ferrer
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K.
Andrew T
AT
Hattersley
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K. sian.ellard@nhs.net.
Sian
S
Ellard
D000595:Amino Acid Sequence; D004247:DNA / Q000378:metabolism; D003920:Diabetes Mellitus / Q000235:genetics*; D050991:GATA4 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006801:Humans; D007231:Infant, Newborn; D008969:Molecular Sequence Data; D009154:Mutation; D010179:Pancreas / Q000002:abnormalities; D011961:Receptors, Fc
D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; C045281:IgA receptor; D011961:Receptors, Fc; D004247:DNA