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. 2024 Nov 26;43(11):114853.
doi: 10.1016/j.celrep.2024.114853. Epub 2024 Oct 19.

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

Sarah Merz  1 , Valérie Senée  2 , Anne Philippi  2 , Franz Oswald  3 , Mina Shaigan  4 , Marita Führer  5 , Cosima Drewes  6 , Chantal Allgöwer  1 , Rupert Öllinger  7 , Martin Heni  8 , Anne Boland  9 , Jean-François Deleuze  9 , Franziska Birkhofer  1 , Eduardo G Gusmao  10 , Martin Wagner  3 , Meike Hohwieler  1 , Markus Breunig  1 , Roland Rad  7 , Reiner Siebert  6 , David Alexander Christian Messerer  11 , Ivan G Costa  4 , Fernando Alvarez  12 , Cécile Julier  13 , Alexander Kleger  14 , Sandra Heller  15
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Free article

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

Sarah Merz et al. Cell Rep. .
Free article

Abstract

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.

Keywords: CP: Developmental biology; CP: Metabolism; ONECUT1; cis-regulatory enhancer; human embryonic stem cells; lncRNA; monogenic diabetes; neonatal diabetes; pancreas differentiation; stem cell islets; type 2 diabetes.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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