Heterozygous Missense Mutations in the Insulin Gene Are Linked to Permanent Diabetes Appearing in the Neonatal Period or in Early Infancy

Abstract

OBJECTIVE—Permanent neonatal diabetes (PND) is defined by chronic hyperglycemia due to severe nonautoimmune insulin deficiency diagnosed in the first months of life. Several genes, including KCNJ11 and ABCC8, which encode the two subunits of the ATP-sensitive K+ channel (KATP channel) can cause PND. Mutations in the insulin (INS) gene have been recently described in families with neonatal diabetes. Our study aimed to investigate the genetic anomalies and clinical heterogeneity in PND patients who are negative for a KATP channel mutation. RESEARCH DESIGN AND METHODS—We screened the INS gene by direct sequencing in 38 PND patients and in one child with nonautoimmune early-infancy diabetes, where no mutation in GCK, KCNJ11, and ABCC8 was identified. A detailed clinical phenotyping of the patients was carried out to specify the diabetes features in those found with an INS mutation. RESULTS—We identified three missense mutations in the INS gene in four probands. Two of four mutations were inherited in a dominant manner, and the familial description evidenced a marked variability in age of diagnosis and disease progression. In our cohort, the INS mutations may represent ∼10% of all permanent neonatal diabetes cases, having a later presentation of diabetes and no associated symptoms compared with cases with KATP channel mutations. CONCLUSIONS—Heterozygous INS gene mutations can cause isolated permanent early-infancy diabetes and should be assessed in neonatal as well as in childhood diabetes appearing like type 1, when autoimmune markers are absent. New pharmacogenomic strategies may be applicable, since residual β-cell function is still present in some patients.

Endoplasmic reticulum stress and the unfolded protein response in pancreatic islet inflammation

“…Moreover, mutations in diverse genes leading to β-cell ER stress contribute to the development of diabetes in humans (Inoue et al 1998, Delepine et al 2000, Stoy et al 2007, Colombo et al 2008, Polak et al 2008. These results suggest that tight control of ER homeostasis is crucial to maintain β-cell function and survival.…”

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.…”

“…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).…”

Diabetes caused by insulin gene (INS) deletion: clinical characteristics of homozygous and heterozygous individuals

“…Furthermore, variation or mutation of the same gene can cause monogenic diabetes but also contribute to individual risk of the very common, polygenic type 2 diabetes (3-7). Recent studies indicated that autosomal dominant insulin gene mutations can cause permanent neonatal diabetes (PND) but also autoantibody-negative diabetes that is classified then as type 1B or maturity-onset diabetes of the young (MODY)-type diabetes (8)(9)(10). The molecular mechanism behind these cases with a MODY-like presentation was suggested to be defective trafficking of proinsulin and increased endoplasmic reticulum (ER) stress (11).…”