Mutations in the Insulin Gene Can Cause MODY and Autoantibody-Negative Type 1 Diabetes
- Anders Molven1,2,
- Monika Ringdal3,4,
- Anita M. Nordbø3,4,
- Helge Ræder5,
- Julie Støy6,
- Gregory M. Lipkind7,
- Donald F. Steiner6,7,
- Louis H. Philipson6,
- Ines Bergmann8,
- Dagfinn Aarskog9,
- Dag E. Undlien10,11,
- Geir Joner12,13,
- Oddmund Søvik3,
- the Norwegian Childhood Diabetes Study Group*,
- Graeme I. Bell6,14 and
- Pål R. Njølstad3,5
- 1Gade Institute, University of Bergen, Norway
- 2Department of Pathology, Haukeland University Hospital, Bergen, Norway
- 3Department of Clinical Medicine, University of Bergen, Bergen, Norway
- 4Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
- 5Department of Pediatrics, Haukeland University Hospital, Bergen, Norway
- 6Department of Medicine, The University of Chicago, Chicago, Illinois
- 7Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, Illinois
- 8Kristiansund Hospital, Kristiansund, Norway
- 9Buskerud Hospital, Drammen, Norway
- 10Institute of Medical Genetics, Faculty Division, Ullevål University Hospital, University of Oslo, Oslo, Norway
- 11Department of Medical Genetics, Ullevål University Hospital, Oslo, Norway
- 12Department of Pediatrics, Ullevål University Hospital, Oslo, Norway
- 13Faculty of Medicine, University of Oslo, Oslo, Norway
- 14Department of Human Genetics, The University of Chicago, Chicago, Illinois
- Address correspondence and reprint requests to Dr. Pål R. Njølstad, Department of Pediatrics, Haukeland University Hospital, N-5021 Bergen, Norway. E-mail:
OBJECTIVE—Mutations in the insulin (INS) gene can cause neonatal diabetes. We hypothesized that mutations in INS could also cause maturity-onset diabetes of the young (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 autoantibody 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 diabetic patients, we found the INS mutation c.163C>T (R55C) in a girl who at 10 years of age presented with ketoacidosis and insulin-dependent, GAD, and insulinoma-associated antigen-2 (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.
- Received October 14, 2007.
- Accepted January 6, 2008.