GATA4 mutations are a cause of neonatal and childhood-onset diabetes

  1. Sian Ellard1
  1. 1Institute of Biomedical and Clinical Science, University of Exeter Medical School, EX2 5DW, UK
  2. 2Genomic Programming of Beta-cells Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
  3. 3CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain
  4. 4Department of Paediatrics, Oncology, Haematology and Diabetology, Medical University of Lodz, Lodz 91-738, Poland
  5. 5Department of Pediatrics, Seattle Children’s Hospital, University of Washington, Seattle, Washington, USA
  6. 6Department of Pediatrics, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands
  7. 7Unidad de Endocrinología Pediátrica. Hospital Universitario Doce de Octubre. Madrid. Spain
  8. 8Molecular (Epi)Genetics Lab, BioAraba National Institute of Health, Hospital Universitario Araba-Txagorritxu, Vitoria-Gasteiz, Spain
  9. 9Division of Applied Medicine, University of Aberdeen, Polwarth Building, Foresterhill, Aberdeen AB25 2ZD, UK
  10. 10Department of Paediatrics, Paediatric Endocrinology and Diabetes, Silesian Medical University, Katowice, Poland
  11. 11Center for Human Genetics, KU Leuven, Leuven B-3000, Belgium
  12. 12Department of Medicine, Imperial College London, London W12 0NN, United Kingdom
  1. Corresponding author: Email: (sian.ellard{at}


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 are also common in patients with GATA4 mutations and deletions but the role of GATA4 in the developing human pancreas is unproven.

We report 5 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 post mortem. 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.


  • * These authors contributed equally

  • Received January 14, 2014.
  • Accepted March 24, 2014.

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