A ONECUT1 regulatory, non-coding region in pancreatic development and diabetes

In a patient with permanent neonatal syndromic diabetes clinically similar to cases with ONECUT1 biallelic mutations, we identified a disease-causing deletion located upstream of ONECUT1. Through genetic, genomic, and functional studies, we identified a crucial regulatory region acting as an enhancer of ONECUT1 specifically during pancreatic development. This enhancer region contains a low-frequency variant showing a strong association with type 2 diabetes and other glycemic traits, thus extending the contribution of this region to common forms of diabetes. Clinical relevance is provided by experimentally tailored therapy options for patients carrying ONECUT1 coding or regulatory mutations. [Display omitted] •Compound heterozygous mutations in ONECUT1 and a non-coding region cause neonatal diabetes•Heterozygous deletion of the non-coding enhancer confirms cis-regulation of ONECUT1 expression•Changes in chromatin looping promote ONECUT1 enhancer activity during pancreatic development•ONECUT1 coding or enhancer mutations affect β cell performance, counteracted by T2D drugs Merz et al. identify a disease-causing deletion upstream of ONECUT1. They uncover a cis-acting enhancer that regulates ONECUT1 expression during pancreatic development, harboring a low-frequency variant associated with type 2 diabetes. Additionally, they provide clinical relevance by experimentally testing in vitro therapeutic options for affected patients.