Insulin Mutation Screening in 1,044 Patients With Diabetes

Abstract

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 Ͻ45 years). None had a molecular genetic diagnosis of monogenic diabetes. RESULTS-We identified heterozygous INS mutations in 33 of141 probands diagnosed at Ͻ6 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 ϩ channel mutation carriers (11 vs. 8 weeks, P Ͻ 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.

Recessive mutations in the INS gene result in neonatal diabetes through reduced insulin biosynthesis

“…Differences in the underlying pathophysiology explain why patients with recessive INS mutations are diagnosed earlier and have a lower birth weight than patients with heterozygous INS mutations (8)(9)(10)(11)(12). The disrupted insulin synthesis seen with recessive mutations occurs as soon as the fetal beta cell starts to secrete insulin.…”

“…In contrast, abnormalities in chromosome 6q24 are the most common cause of TNDM (13), followed by mutations in the KCNJ11 and ABCC8 genes (14). Despite these advances, the etiology of neonatal diabetes is still not known in at least 30% of patients with PNDM, suggesting other genetic causes are still to be found (9).…”

“…Heterozygous missense mutations in the coding region of the INS gene have recently been described as a cause of neonatal diabetes (8)(9)(10)(11)(12). Most of the reported mutations are predicted to disrupt the folding of the proinsulin molecule.…”

“…Recently there have been considerable advances in the understanding of the genetics of neonatal diabetes (3). Most patients with PNDM have activating mutations in KCNJ11 or ABCC8, the genes encoding the potassium ATP-sensitive (K ATP ) channel subunits Kir6.2 (4) and SUR1 (5-7), or heterozygous mutations in the preproinsulin (INS) gene (8)(9)(10)(11)(12). In contrast, abnormalities in chromosome 6q24 are the most common cause of TNDM (13), followed by mutations in the KCNJ11 and ABCC8 genes (14).…”

Amino acid properties may be useful in predicting clinical outcome in patients with Kir6.2 neonatal diabetes

“…Activating mutations in the KCNJ11 and ABCC8 genes, which encode the Kir6.2 and SUR1 subunits of the pancreatic b-cell ATP-sensitive potassium (K ATP ) channel, are the most common cause of NDM accounting for w50% of all cases (2,3,4,5,6,7). In the pancreatic b-cell, glucose metabolism results in an increase in the concentration of intracellular ATP.…”