biostudies-literatureMeur GNIDDK NIH HHSMedical Research CouncilWellcome Trust653-61https://www.ebi.ac.uk/biostudies/studies/S-EPMC2828668biostudies-literatureUnknown59(3)<h4>Objective</h4>Heterozygous mutations in the human preproinsulin (INS) gene are a cause of nonsyndromic neonatal or early-infancy diabetes. Here, we sought to identify INS mutations associated with maturity-onset diabetes of the young (MODY) or nonautoimmune diabetes in mid-adult life, and to explore the molecular mechanisms involved.<h4>Research design and methods</h4>The INS gene was sequenced in 16 French probands with unexplained MODY, 95 patients with nonautoimmune early-onset diabetes (diagnosed at <35 years) and 292 normoglycemic control subjects of French origin. Three identified insulin mutants were generated by site-directed mutagenesis of cDNA encoding a preproinsulin-green fluorescent protein (GFP) (C-peptide) chimera. Intracellular targeting was assessed in clonal beta-cellDiabetesInsulin gene mutations resulting in early-onset diabetes: marked differences in clinical presentation, metabolic status, and pathogenic effect through endoplasmic reticulum retention.PMC2828668R01 DK071962G0401641081958/2/07/ZG0700342081958G0600331R01 DK-071962-01Fetita SHarun NPedersen OGuillausseau PJGautier JFVirally MSimon AHansen TBonnefond AVaxillaire MTarasov AIMeur GRutter GABoesgaard TWPolak MDechaume AFroguel PfalseInsulin gene mutations resulting in early-onset diabetes: marked differences in clinical presentation, metabolic status, and pathogenic effect through endoplasmic reticulum retention.<h4>Objective</h4>Heterozygous mutations in the human preproinsulin (INS) gene are a cause of nonsyndromic neonatal or early-infancy diabetes. Here, we sought to identify INS mutations associated with maturity-onset diabetes of the young (MODY) or nonautoimmune diabetes in mid-adult life, and to explore the molecular mechanisms involved.<h4>Research design and methods</h4>The INS gene was sequenced in 16 French probands with unexplained MODY, 95 patients with nonautoimmune early-onset diabetes (diagnosed at <35 years) and 292 normoglycemic control subjects of French origin. Three identified insulin mutants were generated by site-directed mutagenesis of cDNA encoding a preproinsulin-green fluorescent protein (GFP) (C-peptide) chimera. Intracellular targeting was assessed in clonal beta-cell2010-01-01T00:00:00Z2010 Mar2026-06-04T03:44:03.359Z2026-05-06T03:13:11.197ZS-EPMC28286682000793610.2337/db09-1091