Variants in the gene ONECUT1 cause both, dominant and recessive forms of monogenic diabetes mellitus and are also involved in the development of multifactorial diabetes. These are results of an international study recently published in Nature Medicine. By comprehensive genetic studies and functional investigations using, among others, induced pluripotent stem cells, researchers unravelled the importance of one cut homeobox 1, the protein encoded by ONECUT1, in the proper development and functioning of the pancreas.

In this study, causative homozygous mutations in ONECUT1 were identified in two unrelated patients with a severe form of neonatal syndromic diabetes. In family members carrying the mutations in heterozygous state, they resulted in early-onset diabetes manifesting in early adulthood. The study also found that common variants in regulatory regions of ONECUT1 are associated with multifactorial type-2 diabetes. On a molecular level, the researchers detected that the identified mutations impair the formation of pancreatic progenitor cells and the function of insulin-producing beta cells. They also altered expression of other transcription factors (NKX2.2, NKX6.1) that are also essential in pancreatic development.