Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Brief Communication
  • Published:

GATA6 haploinsufficiency causes pancreatic agenesis in humans

Abstract

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

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

Similar content being viewed by others

References

  1. Sellick, G.S. et al. Nat. Genet. 36, 1301–1305 (2004).

    Article  CAS  Google Scholar 

  2. Stoffers, D.A. et al. Nat. Genet. 15, 106–110 (1997).

    Article  CAS  Google Scholar 

  3. Thomas, I.H. et al. Pediatr. Diabetes 10, 492–496 (2009).

    Article  CAS  Google Scholar 

  4. Balasubramanian, M. et al. Am. J. Med. Genet. A. 152A, 340–346 (2010).

    Article  CAS  Google Scholar 

  5. Kodo, K. et al. Proc. Natl. Acad. Sci. USA 106, 13933–13938 (2009).

    Article  CAS  Google Scholar 

  6. Lin, X. et al. J. Hum. Genet. 55, 662–667 (2010).

    Article  CAS  Google Scholar 

  7. Maitra, M. et al. Pediatr. Res. 68, 281–285 (2010).

    Article  CAS  Google Scholar 

  8. Morrisey, E.E. et al. Genes Dev. 12, 3579–3590 (1998).

    Article  CAS  Google Scholar 

  9. Watt, A.J. et al. BMC Dev. Biol. 7, 37 (2007).

    Article  Google Scholar 

  10. Decker, K. et al. Dev. Biol. 298, 415–429 (2006).

    Article  CAS  Google Scholar 

  11. Rubio-Cabezas, O. et al. Diabetes 60, 1349–1353 (2011).

    Article  CAS  Google Scholar 

  12. Rubio-Cabezas, O. et al. Diabetes 59, 2326–2331 (2010).

    Article  Google Scholar 

  13. Servitja, J.M. & Ferrer, J. Diabetologia 47, 597–613 (2004).

    Article  CAS  Google Scholar 

  14. Zhou, Q. et al. Nature 455, 627–632 (2008).

    Article  CAS  Google Scholar 

  15. Kroon, E. et al. Nat. Biotechnol. 26, 443–452 (2008).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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).

Author information

Authors and Affiliations

Authors

Consortia

Contributions

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.

Corresponding author

Correspondence to Andrew T Hattersley.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

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

Supplementary information

Supplementary Text and Figures

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

Rights and permissions

Reprints and permissions

About this article

Cite this article

Allen, H., Flanagan, S., Shaw-Smith, C. et al. GATA6 haploinsufficiency causes pancreatic agenesis in humans. Nat Genet 44, 20–22 (2012). https://doi.org/10.1038/ng.1035

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.1035

This article is cited by

Search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research