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GATA6 haploinsufficiency causes pancreatic agenesis in humans


Understanding the regulation of pancreatic development is key for efforts to develop new regenerative therapeutic approaches for diabetes. Rare mutations in PDX1 and PTF1A can cause pancreatic agenesis, however, most instances of this disorder are of unknown origin. We report de novo heterozygous inactivating mutations in GATA6 in 15/27 (56%) individuals with pancreatic agenesis. These findings define the most common cause of human pancreatic agenesis and establish a key role for the transcription factor GATA6 in human pancreatic development.

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Figure 1: GATA6 mutations causing pancreatic agenesis.
Figure 2: Clinical characteristics of the pancreatic agenesis cohort.


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The authors thank the families who participated in this study. We are grateful to A. Damhuis, A. Moorhouse and K. Paszkiewicz for their expert technical assistance. We thank H. Yamagishi (Keio University, Japan) for providing the GATA6 plasmid. S.E.F. was the Sir Graham Wilkins, Peninsula Medical School Research Fellow. S.E. and A.T.H. are employed as core members of staff within the National Institute for Health Research–funded Peninsula Clinical Research Facility. The research leading to these results received funding from Diabetes UK, the Wellcome Research Leave Award for Clinical Academics (ref 067463/Z/2/Z) and the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement number 223211 (Collaborative European Effort to Develop Diabetes Diagnostics, CEED3) and grant agreement number FP7-PEOPLE-ITN-2008 (Marie Curie Initial Training Networks, Biology of Liver and Pancreatic Development and Disease).

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S.E., S.E.F., J.F. and A.T.H. designed the study. R.C. performed the exome sequencing and the structural modeling. H.L.A. did the bioinformatic analyses. E.D.F. and S.E.F. did the Sanger sequencing analysis and the interpretation of the resulting data. C.S.-S. and A.T.H. analyzed the clinical data. I.A. and J.F. performed the functional studies. H.L.A., C.S.-S., J.F., A.T.H. and S.E. prepared the draft manuscript. All authors contributed to the discussion of the results and the manuscript preparation.

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Correspondence to Andrew T Hattersley.

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The authors declare no competing financial interests.

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A full list of members is provided in the Supplementary Note.

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Supplementary Note, Supplementary Methods, Supplementary Figures 1–3 and Supplementary Tables 1–4. (PDF 399 kb)

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Allen, H., Flanagan, S., Shaw-Smith, C. et al. GATA6 haploinsufficiency causes pancreatic agenesis in humans. Nat Genet 44, 20–22 (2012).

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