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Mutations in the Insulin Gene can Cause MODY and Autoantibody-Negative Type 1 Diabetes

From the ¹Gade Institute, University of Bergen, Norway
the ²Department of Pathology, Haukeland University Hospital, Bergen, Norway
the ³Department of Clinical Medicine, University of Bergen, Bergen, Norway
the ⁴Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
the ⁵Department of Pediatrics, Haukeland University Hospital, Bergen, Norway
the Departments of ⁶Medicine
⁷Human Genetics and
⁸Biochemistry and Molecular Biology, The University of Chicago, Chicago, Illinois, USA
⁹Kristiansund Hospital, Kristiansund, Norway
¹⁰Buskerud Hospital, Drammen, Norway
the ¹¹Institute of Medical Genetics, Faculty Division, Ullevål University Hospital, University of Oslo, Oslo, Norway
the ¹²Department of Medical Genetics, Ullevål University Hospital, Oslo, Norway
the ¹³Department of Pediatrics, Ullevål University Hospital, Oslo, Norway; and
the ¹⁴Faculty of Medicine, University of Oslo, Oslo, Norway

Objective: Mutations in the insulin (INS) gene can cause neonatal diabetes. We hypothesized that mutations in INS could also cause MODY and autoantibody-negative type 1 diabetes.

Research Design And Methods: We screened INS in 62 probands with MODY, 30 probands with suspected MODY, and 223 subjects from the Norwegian Childhood Diabetes Registry selected on the basis of auto-antibody negativity or family history of diabetes.

Results: Among the MODY patients, we identified the INS mutation c.137G>A (R46Q) in a proband, his diabetic father and a paternal aunt. They were diagnosed with diabetes at 20, 18 and 17 years of age, respectively, and are treated with small doses of insulin or diet only. In type 1 diabetes patients, we found the INS mutation c.163C>T (R55C) in a girl who 10 years old presented with ketoacidosis and insulin-dependent, GAD and IA-2 antibody-negative diabetes. Her mother had a de novo R55C mutation and was diagnosed with ketoacidosis and insulin-dependent diabetes at 13 years of age. Both had residual β–cell function. The R46Q substitution changes an invariant arginine residue in position B22, which forms a hydrogen bond with the glutamate at A17 stabilizing the insulin molecule. The R55C substitution involves the first of the two arginine residues localized at the site of proteolytic processing between the B-chain and the C-peptide.

Conclusions: Our findings extend the phenotype of INS mutation carriers and suggest that INS screening is warranted not only in neonatal diabetes, but also in MODY and in selected cases of type 1 diabetes.

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