An international team under German-French leadership has discovered that mutations in the ONECUT1 gene can trigger some forms of diabetes. Such genetic defects lead to a malfunction of the pancreas and impede insulin production by the beta cells. The study, in which researchers from the Ulm University Medical Centre played a leading role, was published in the renowned journal “Nature Medicine”. The journal is among the leading international journals in the field of medicine with an impact factor of more than 53. The results of the study can help specialists to personalise diabetes therapies.

Diabetes mellitus is a widespread disease. In Germany, more than seven percent of adults suffer from this chronic metabolic disease and children are also becoming increasingly afflicted. The disease is associated with high blood sugar levels, which are connected to serious secondary diseases in the long term. The causes, symptoms and courses of the disease differ by the type of diabetes. In addition to the more common forms of diabetes, known as type 1 and type 2 diabetes, there are also other rare forms whereby the disease is monogenetic, ie it is triggered by a single genetic defect.

An international research team has now been able to demonstrate in a study published in “Nature Medicine” that mutations in the ONECUT1 gene play a key role in the development of certain forms of diabetes. The researchers identified genetic defects in ONECUT1 not only in patient groups with monogenetic diabetes. They were also able to prove that variants of this gene play an important role in special forms of type 2 diabetes that appear in early adulthood.

A discovery with major clinical relevance

“In our study, we were able to identify a human diabetes gene that was previously unknown,” explains Heisenberg Professor Alexander Kleger, head of the pancreatic research team at the Clinic for Internal Medicine I at the Ulm University Medical Centre. “This is a discovery with major clinical relevance, because it can help us to personalise treatment of diabetes, taking into account the genetic characteristics of the individual,” the physician adds. Kleger led the study in cooperation with Dr Cécile Julier, a human geneticist at the renowned Cochin Institute in Paris. Not only were the researchers successful in detecting this specific genetic defect in humans with diabetes, but they were also able to shed more light on the mechanism by which the ONECUT1 variants impair the function of the insulin-producing beta cells. The ONECUT1 gene plays an important role in the development of the pancreas. Mutations in this important gene disrupt the complex process at various stages.

In order to better understand the molecular-genetic networks of pancreatic development, human pluripotent stem cells with the deactivated ONECUT1 gene were differentiated into pancreatic cells. Skin cells were also taken from the patients and reprogrammed into stem cells, which were then further developed into pancreatic cells. These complex laboratory investigations revealed that the development of pancreatic progenitor cells was significantly impeded by the newly discovered ONECUT1 gene variant and that the pancreas’s insulin-producing beta cells were permanently disrupted in their function of regulating blood sugar levels.

The research team was also able to decipher the molecular-genetic mechanisms that trigger this dysfunction. “It became apparent that mutations in the ONECUT1 gene prevented other transcription factors from binding to the DNA, causing the pancreas-specific gene expression regulators to be reduced in their activity,” explains Dr Sandra Heller, a researcher from Ulm who is one of the four first authors of the “Nature Medicine” publication, along with the bioinformaticist Professor Ivan Costa from the Aachen University Medical Centre.

A milestone for personalized diabetes therapy

“The result of this joint study is a milestone. It demonstrates how cooperation between specialists in the fields of clinical medicine, human genetics and patient-oriented basic research can help to provide a better understanding of a complex metabolic disease. Suspected cases of type 2 diabetes, for instance, turn out to be cases of monogenetic diabetes upon closer inspection. This is significant in terms of managing therapies for the afflicted,” the researchers reveal.

Researchers from Germany, France, the USA, Lebanon, the United Arab Emirates, Austria and Singapore were involved in this international and interdisciplinary joint project. Professor Alexander Kleger led the functional part of the study, while Dr Cécile Julier was responsible for the genetic part. For the study, a French index family was characterised by Professor Marc Nicolino. A cohort of patients from Baden-Württemberg with early-onset type 2 diabetes was recruited by Professor Bernhard Böhm. The researchers received substantial support through a collaborative project with the French Agence Nationale de la Recherche (ANR) and the German Research Foundation (Deutsche Forschungsgesellschaft, DFG), as well as from the Boehringer Ingelheim Ulm University BioCenter, “BIU 2.0”.

To provide some context: the ONECUT1 gene codes for a protein with the name of One cut homeobox 1. This protein acts as a so-called transcription factor, which determines, dependent on whether it is on or off, if certain genes are active or not. Transcription factors in general ensure that the genetic information of the DNA is transformed into so-called messenger-RNA in the right cell, at the right time and in the right amount. This mRNA, in turn, provides the blueprints for the biosynthesis of certain proteins, which themselves then fulfil a variety of functions. ONECUT1 is one part of an entire family of genes that code for proteins which play an equally important role in the development of the pancreas and the liver.

Literature:
Mutations and variants of ONECUT1 in diabetes
A. Philippi, S. Heller, I. G. Costa, V. Senée, M. Breunig, Z. Li, G. Kwon, R. Russell, A. Illing, Q. Lin, M. Hohwieler, A. Degavre, P. Zalloua, S. Liebau, M. Schuster, J. Krumm, X. Zhang, R. Geusz, J. R. Benthuysen, A. Wang, J. Chiou, K. Gaulton, H. Neubauer, E. Simon, Th. Klein, M. Wagner, G. Nair, C. Besse, C. Dandine-Roulland, R. Olaso, J.-F. Deleuze, B. Kuster, M. Hebrok, Th. Seufferlein, M. Sander, B. O. Boehm, F. Oswald, M. Nicolino, C. Julier, A. Kleger, In: Nature Medicine, 18 October 2021

doi.org/10.1038/s41591-021-01502-7
view-only version of the paper

Text and mediacontact: Andrea Weber-Tuckermann