Rare genetic change provides clues to pancreas development

Understanding pancreas formation could aid research into type 1 diabetes treatments

Researchers have discovered a key clue into the development of the pancreas and brain by studying rare patients born without a pancreas. The study from the Wellcome Sanger Institute, the University of Exeter and collaborators also identified a previously unexpected pathway involved in the development of the human pancreas, and confirmed this in mice. Understanding how the human pancreas forms could help researchers develop replacement cells to treat patients with type 1 diabetes in the future.

Published today (18th April) in the American Journal of Human Genetics, the study revealed that all three patients without a pancreas and with abnormal brain development had an identical change in the CNOT1 gene. The team went on to show how this genetic change kept stem cells in their original state, preventing them from developing into pancreatic cells.

The pancreas is part of the digestive system and makes various hormones, including insulin that controls the amount of sugar in the blood. Problems with the insulin producing cells in the pancreas can cause type 1 diabetes, which affects over 10 million people worldwide.

Type 1 diabetes develops when insulin-making cells in the pancreas, called beta cells, are attacked by the immune system. People with this disease need daily injections of insulin to control their blood sugar levels. Replacing the damaged pancreatic cells with cells derived from stem cells could treat the disease, but the pancreatic development pathways are not yet fully known.

In very rare cases, the pancreas fails to develop – called pancreatic agenesis – and babies born with this condition need immediate and lifelong treatment with insulin and other hormones to survive.

To learn more about the development of the pancreas, researchers from the University of Exeter studied the genetics of 107 international patients with pancreatic agenesis. They discovered that three unrelated patients with very similar clinical features, including a possible neurological disorder, had an identical mutation in the CNOT1 gene. This gene had never been implicated in pancreatic or brain development before.

The Wellcome Sanger Institute researchers then bred mice with this mutation in the mouse version of the gene to see how it affected development. They found the mouse embryos with the mutation in Cnot1* had a much smaller upper pancreas than usual, directly linking the Cnot1 gene with pancreas development. They also saw changes in the mouse brain development.

“We found that three patients with pancreatic agenesis had an identical spelling mistake in the CNOT1 gene. This was the first time that anyone had realised that CNOT1 was important in pancreatic and neurological development, and has revealed a new genetic cause for pancreatic agenesis.”

Dr Elisa De Franco Co-first author from the University of Exeter Medical School

“Through a great collaboration between clinical and mouse research disciplines, we have provided compelling evidence that the CNOT1 gene is involved in the formation of the pancreas in both humans and mice. We are now able to investigate the developmental mechanism, to understand how the pancreas develops.”

Dr Inês Barroso Co-senior author on the paper from the Wellcome Sanger Institute** and University of Cambridge

The CNOT1 gene had previously been implicated in keeping human and mice embryonic stem cells in a state where they can develop into any type of cell, known as pluripotency. Studying which genes were active in the developing mouse pancreas, the researchers discovered that the Cnot1 mutation changed the levels of a key developmental factor, preventing the stem cells from developing.

“Once we knew the CNOT1 gene was involved in pancreatic development, we wanted to find out how it worked. Changes in some developmental factors in Cnot1 mutant mice indicated that the stem cells remained as stem cells, rather than developing into pancreatic cells. This suggested an entirely new mechanism for pancreatic agenesis, which involved maintaining stem cells in a pluripotent state.”

Dr Rachel Watson A joint first author from the Wellcome Sanger Institute

“In the future, therapies that created new pancreatic beta cells, could end the need for insulin injections for millions of people with type 1 diabetes. This type of therapy would require a very good understanding of how the pancreas develops. Our multidisciplinary collaboration has allowed us to unravel a new gene and mechanism involved in pancreas development, and revealed further avenues for investigation.”

Professor Andrew Hattersley Co-senior author on the paper from the University of Exeter Medical School

More information


Elisa De Franco & Rachel Watson et al. (2019) A specific CNOT1 mutation results in a novel syndrome of pancreatic agenesis and holoprosencephaly through impaired pancreatic and neurological development. American Journal of Human Genetics. DOI: 10.1016/j.ajhg.2019.03.018

* The symbols for human genes are written in capital letters, eg CNOT1, whereas the symbol for mouse genes only have a capital first letter, eg Cnot1. These two genes are very similar, but not identical.

** Dr Inês Barroso carried out the work at the Wellcome Sanger Institute and is now based at the MRC Epidemiology Unit at the University of Cambridge.


This work was supported by Wellcome, the NIHR, a Naomi Berrie Fellowship in Diabetes Research, the Royal Society, Research Foundation-Flanders, the VUB Research Council and Stichting Diabetes Onderzoek Nederland.

Selected websites

  • About the University of Exeter Medical School

    The University of Exeter Medical School is improving the health of the South West and beyond, through the development of high quality graduates and world-leading research that has international impact.

    As part of a Russell Group university, we combine this world-class research with very high levels of student satisfaction. Part of the University of Exeter’s College for Medicine and Health, the University of Exeter Medical School’s Medicine programme is ranked 5th in the Guardian Guide 2018, while Medical Imaging is ranked 2nd, in the Complete University Guide 2018, under Radiography. Exeter has over 19,000 students and is ranked 12th in The Times and The Sunday Times Good University Guide 2018. In the 2014 Research Excellence Framework (REF), the University ranked 16th nationally, with 98% of its research rated as being of international quality. Exeter’s Clinical Medicine research was ranked 3rd in the country, based on research outputs that were rated world-leading. Public Health, Health Services and Primary Care research also ranked in the top ten, in joint 9th for research outputs rated world-leading or internationally excellent. https://medicine.exeter.ac.uk/

  • The Wellcome Sanger Institute

    The Sanger Institute is one of the world’s leading genome and biodata institutes. Through its ability to conduct research at scale, it is able to engage in bold and long-term exploratory projects that are designed to influence and empower science globally. Institute research findings, generated through its own research programmes and through its leading role in international consortia, are being used to develop new diagnostics and treatments for human disease and to understand life on Earth. Find out more at www.sanger.ac.uk or follow @sangerinstitute on Twitter, Facebook, LinkedIn and on our Blog.

  • About Wellcome

    Wellcome exists to improve health by helping great ideas to thrive. We support researchers, we take on big health challenges, we campaign for better science, and we help everyone get involved with science and health research. We are a politically and financially independent foundation. https://wellcome.org/