A New Form of Diabetes Caused by INS Mutations Defined by Zygosity, Stem Cell and Population Data

ABSTRACT: The INS c.16C>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 a

SUBMITTER: Yue Tong 

PROVIDER: S-SCDT-10_1038-S44321-025-00362-9 | biostudies-other |

REPOSITORIES: biostudies-other