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.
Authors
- David Alexander Christian Messerer (ORCID: https://orcid.org/0000-0002-0834-038X)
- Markus Breunig (ORCID: https://orcid.org/0000-0002-2817-1974)
- Sandra Heller (ORCID: https://orcid.org/0000-0002-8704-2646)
- Martin Heni (ORCID: https://orcid.org/0000-0002-8462-3832)
- Meike Hohwieler (ORCID: https://orcid.org/0000-0002-0640-0764)
- Eduardo Gade Gusmao (ORCID: https://orcid.org/0000-0001-7461-1443)
- Fernando Álvarez Guisasola (ORCID: https://orcid.org/0000-0002-0872-8245)
- Anne Philippi (ORCID: https://orcid.org/0000-0003-2184-6008)
- Chantal Allgöwer
- Rupert Öllinger (ORCID: https://orcid.org/0000-0002-2292-5982)
- Marita Führer (ORCID: https://orcid.org/0000-0002-3423-0854)
- Cosima Drewes
- Valérie Senée (ORCID: https://orcid.org/0000-0001-7012-3944)
- Alexander Kleger (ORCID: https://orcid.org/0000-0003-0592-5232)
- Franz Oswald (ORCID: https://orcid.org/0000-0002-2923-5765)
- Ivan G. Costa (ORCID: https://orcid.org/0000-0003-2890-8697)
- Cécile Julier (ORCID: https://orcid.org/0000-0002-1538-0240)
- Sarah K. Merz (ORCID: https://orcid.org/0000-0002-9414-2880)
- Roland Rad (ORCID: https://orcid.org/0000-0002-6849-9659)
- Reiner Siebert (ORCID: https://orcid.org/0000-0002-6492-5323)
- Martin Wagner (ORCID: https://orcid.org/0000-0001-5735-3462)
- Franziska Birkhofer
- Mina Shaigan
- Jean-François Deleuze
- Anne Boland
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Universität Ulm (DE)
- Université Paris Cité (FR)
- Universidade Federal de Pernambuco (BR)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Université Paris-Saclay (FR)
- German Red Cross (DE)
- Centre Hospitalier Universitaire Sainte-Justine (CA)
- Centre National de Recherche en Génomique Humaine (FR)
- Immungenetics (Germany) (DE)
- CEA Paris-Saclay (FR)
- Institut Cochin (FR)
- University Hospital Ulm (DE)
- Technical University of Munich (DE)
- University of Tübingen (DE)
- RWTH Aachen University (DE)
Publication Details
- Journal
- Cell Reports
- Published
- 2024-10-19
- DOI
- https://doi.org/10.1016/j.celrep.2024.114853
- Citations
- 2
- Primary Topic
- Pancreatic function and diabetes
- Type
- article
- Field-Weighted Citation Impact
- 1.15
Funders
- European Foundation for the Study of Diabetes
- Deutsche Forschungsgemeinschaft
- Agence Nationale de la Recherche
- Else Kröner-Fresenius-Stiftung
- Novo Nordisk
- Hospices Civils de Lyon
- Universität Ulm
- Assistance publique-Hôpitaux de Paris