Insulin Mutation Screening in 1,044 Patients With Diabetes
Mutations in the INS Gene Are a Common Cause of Neonatal Diabetes but a Rare Cause of Diabetes Diagnosed in Childhood or Adulthood
- Emma L. Edghill1,
- Sarah E. Flanagan1,
- Ann-Marie Patch1,
- Chris Boustred1,
- Andrew Parrish1,
- Beverley Shields1,
- Maggie H. Shepherd2,
- Khalid Hussain3,
- Ritika R. Kapoor3,
- Maciej Malecki4,
- Michael J. MacDonald5,
- Julie Støy6,
- Donald F. Steiner6,7,
- Louis H. Philipson6,
- Graeme I. Bell6,8,
- the Neonatal Diabetes International Collaborative Group*,
- Andrew T. Hattersley1 and
- Sian Ellard1
- 1Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, U.K
- 2Institute of Health and Social Care, Peninsula Medical School, Exeter, U.K
- 3Department of Endocrinology, Great Ormond Street Hospital for Children NHS Trust and the Institute of Child Health, University College London, London, U.K
- 4Department of Metabolic Diseases, Jagiellonian University, Krakow, Poland
- 5Department of Pediatrics, University of Wisconsin Medical School, Madison, Wisconsin
- 6Department of Medicine, The University of Chicago, Chicago, Illinois
- 7Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, Illinois
- 8Department of Human Genetics, The University of Chicago, Chicago, Illinois
- Address correspondence and reprint requests to Prof. Andrew T. Hattersley, Institute of Biomedical and Clinical Science, Peninsula Medical School, Barrack Road, Exeter EX2 5DW, U.K. E-mail:
OBJECTIVE— Insulin gene (INS) mutations have recently been described as a cause of permanent neonatal diabetes (PND). We aimed to determine the prevalence, genetics, and clinical phenotype of INS mutations in large cohorts of patients with neonatal diabetes and permanent diabetes diagnosed in infancy, childhood, or adulthood.
RESEARCH DESIGN AND METHODS— The INS gene was sequenced in 285 patients with diabetes diagnosed before 2 years of age, 296 probands with maturity-onset diabetes of the young (MODY), and 463 patients with young-onset type 2 diabetes (nonobese, diagnosed <45 years). None had a molecular genetic diagnosis of monogenic diabetes.
RESULTS— We identified heterozygous INS mutations in 33 of 141 probands diagnosed at <6 months, 2 of 86 between 6 and 12 months, and none of 58 between 12 and 24 months of age. Three known mutations (A24D, F48C, and R89C) account for 46% of cases. There were six novel mutations: H29D, L35P, G84R, C96S, S101C, and Y103C. INS mutation carriers were all insulin treated from diagnosis and were diagnosed later than ATP-sensitive K+ channel mutation carriers (11 vs. 8 weeks, P < 0.01). In 279 patients with PND, the frequency of KCNJ11, ABCC8, and INS gene mutations was 31, 10, and 12%, respectively. A heterozygous R6C mutation cosegregated with diabetes in a MODY family and is probably pathogenic, but the L68M substitution identified in a patient with young-onset type 2 diabetes may be a rare nonfunctional variant.
CONCLUSIONS— We conclude that INS mutations are the second most common cause of PND and a rare cause of MODY. Insulin gene mutation screening is recommended for all diabetic patients diagnosed before 1 year of age.
- ER, Endoplasmic Reticulum
- ISPAD, International Society of Pediatric and Adolescent Diabetes
- KATP channel, ATP-sensitive K+ channel
- MODY, Maturity-Onset Diabetes of the Young
- PND, permanent neonatal diabetes
- Received October 3, 2007.
- Accepted December 14, 2007.