A new form of diabetes caused by INS mutations defined by zygosity, stem cell and population data
The INS c.16 C > T (insulin p.Arg6Cys, R6C) variant was reported to cause autosomal dominant monogenic diabetes, yet its pathogenicity has been questioned. R6C preproinsulin exhibits impaired translocation into the endoplasmic reticulum (ER). We explored R6C pathogenicity using integrative clinical, genetic, and functional approaches.Homozygous INS R6C individuals presented early-onset insulin-treated diabetes, whereas heterozygous carriers showed variable or absent glycemic phenotypes. Population-level analysis revealed no significant enrichment of diabetes among heterozygotes. Heterozygous R6C patient's induced pluripotent stem cell (iPSC)-derived pancreatic β cells exhibited minimal defects, while homozygous R6C β cells displayed preproinsulin accumulation and reduced insulin content and secretion. In vivo, homozygous R6C β cell transplants recapitulated insulin deficiency and responded poorly to GLP-1 receptor agonist. Homozygous R6C β cells had a gene signature of attenuated translation, translocation and ER related pathways.Our findings establish R6C as a recessive loss-of-function mutation, prompting a clinical reassessment of heterozygous R6C carriers. This study highlights the power of population genetic databases, patients' iPSC-based modeling and multi-modal variant classification frameworks for dissecting the consequences of genetic variants in monogenic diabetes.
Authors
- Chiara Vinci (ORCID: https://orcid.org/0000-0002-5730-9186)
- Flávia Natividade da Silva (ORCID: https://orcid.org/0000-0002-8583-1692)
- Kevin Colclough (ORCID: https://orcid.org/0000-0003-0566-4853)
- Raphaël Scharfmann (ORCID: https://orcid.org/0000-0001-7619-337X)
- Leena Haataja (ORCID: https://orcid.org/0000-0003-3701-4679)
- Timo Otonkoski (ORCID: https://orcid.org/0000-0001-9190-2496)
- Maria Lytrivi (ORCID: https://orcid.org/0000-0002-0234-8372)
- María Nicol Arroyo
- Miriam Cnop (ORCID: https://orcid.org/0000-0002-5112-1692)
- Federica Fantuzzi (ORCID: https://orcid.org/0000-0003-3202-3947)
- Peter Arvan (ORCID: https://orcid.org/0000-0002-4007-8799)
- Hossam Montaser (ORCID: https://orcid.org/0000-0003-0879-1807)
- Ulrike Helga Elisabeth Schierloh (ORCID: https://orcid.org/0000-0002-7644-4818)
- F. Kobaisi
- Ying Cai (ORCID: https://orcid.org/0000-0001-8766-6005)
- Igoillo-Esteve Mariana
- Muhammad Javed
- de Beaufort Carine
- Nathalie Pachera
- Marianne Becker
- Andrew T Hattersley
- Kashyap A Patel
- Uyenlinh L Mirshahi
- Xiaoyan Yi
- Toshiaki Sawatani
- Yue Tong
- Matthew N Wakeling
Institutions
- Centre National de la Recherche Scientifique (FR)
- Université Libre de Bruxelles (BE)
- University of Helsinki (FI)
- Inserm (FR)
- Centre Hospitalier de Luxembourg (LU)
- Université Paris Cité (FR)
- University of Exeter (GB)
- University of Michigan (US)
- Royal Devon & Exeter NHS Foundation Trust (GB)
- Helsinki University Hospital (FI)
- Erasmus Hospital (BE)
- Institut Cochin (FR)
- Walloon Excellence in Lifesciences and Biotechnology (BE)
- Walsall Healthcare NHS Trust (GB)
- Genomic Health (United States) (US)
- Geisinger Health System (US)
Publication Details
- Journal
- EMBO Molecular Medicine
- Published
- 2026-01-03
- DOI
- https://doi.org/10.1038/s44321-025-00362-9
- Primary Topic
- Pancreatic function and diabetes
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Leona M. and Harry B. Helmsley Charitable Trust
- Helsingin Yliopisto
- European Federation of Pharmaceutical Industries and Associations
- National Institute for Health and Care Research
- European Commission
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Fonds De La Recherche Scientifique - FNRS
- Fonds Wetenschappelijk Onderzoek
- Vlaamse regering
- Walloon excellence in life sciences and biotechnology
- National Institutes of Health
- Fonds pour la Formation à la Recherche dans l’Industrie et dans l’Agriculture
- ULB Center for Diabetes Research