A new form of diabetes caused by INS mutations defined by zygosity, stem cell and population data
Tong, Yue Becker, Marianne Schierloh, Ulrike Natividade da Silva, Flávia Haataja, Leena Cai, Ying Patel, Kashyap A Kobaisi, Farah Mirshahi, Uyenlinh L Colclough, Kevin
Tong, Yue
Becker, Marianne
Schierloh, Ulrike
Natividade da Silva, Flávia
Haataja, Leena
Cai, Ying
Patel, Kashyap A
Kobaisi, Farah
Mirshahi, Uyenlinh L
Colclough, Kevin
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Affiliation
Université Libre de Bruxelles; Centre Hospitalier de Luxembourg; University of Michigan Medical School; University of Exeter; Université Paris Cité; Royal Devon University Healthcare NHS Foundation Trust; Walsall Healthcare NHS Trust; ULB Erasmus Hospital; University of Helsinki; Brussels University Hospital; WEL Research Institute
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2026-01-03
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Abstract
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.
Citation
Tong Y, Becker M, Schierloh U, Natividade da Silva F, Haataja L, Cai Y, Patel KA, Kobaisi F, Mirshahi UL, Colclough K, Javed MS, Wakeling MN, Fantuzzi F, Lytrivi M, Sawatani T, Arroyo MN, Yi X, Vinci C, Montaser H, Pachera N, Otonkoski T, Igoillo-Esteve M, Scharfmann R, Hattersley AT, Arvan P, De Beaufort C, Cnop M. A new form of diabetes caused by INS mutations defined by zygosity, stem cell and population data. EMBO Mol Med. 2026 Jan 3. doi: 10.1038/s44321-025-00362-9. Epub ahead of print. PMID: 41484206.
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Article