Dataset Information

Update of variants identified in the pancreatic ?-cell KATP channel genes KCNJ11 and ABCC8 in individuals with congenital hyperinsulinism and diabetes.

ABSTRACT: The most common genetic cause of neonatal diabetes and hyperinsulinism is pathogenic variants in ABCC8 and KCNJ11. These genes encode the subunits of the ?-cell ATP-sensitive potassium channel, a key component of the glucose-stimulated insulin secretion pathway. Mutations in the two genes cause dysregulated insulin secretion; inactivating mutations cause an oversecretion of insulin, leading to congenital hyperinsulinism, whereas activating mutations cause the opposing phenotype, diabetes. This review focuses on variants identified in ABCC8 and KCNJ11, the phenotypic spectrum and the treatment implications for individuals with pathogenic variants.

SUBMITTER: De Franco E

PROVIDER: S-EPMC7187370 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Update of variants identified in the pancreatic β-cell K<sub>ATP</sub> channel genes KCNJ11 and ABCC8 in individuals with congenital hyperinsulinism and diabetes.

De Franco Elisa E Saint-Martin Cécile C Brusgaard Klaus K Knight Johnson Amy E AE Aguilar-Bryan Lydia L Bowman Pamela P Arnoux Jean-Baptiste JB Larsen Annette Rønholt AR Sanyoura May M Greeley Siri Atma W SAW Calzada-León Raúl R Harman Bradley B Houghton Jayne A L JAL Nishimura-Meguro Elisa E Laver Thomas W TW Ellard Sian S Del Gaudio Daniela D Christesen Henrik Thybo HT Bellanné-Chantelot Christine C Flanagan Sarah E SE

Human mutation 20200217 5

The most common genetic cause of neonatal diabetes and hyperinsulinism is pathogenic variants in ABCC8 and KCNJ11. These genes encode the subunits of the β-cell ATP-sensitive potassium channel, a key component of the glucose-stimulated insulin secretion pathway. Mutations in the two genes cause dysregulated insulin secretion; inactivating mutations cause an oversecretion of insulin, leading to congenital hyperinsulinism, whereas activating mutations cause the opposing phenotype, diabetes. This r ...[more]

PMID: 32027066

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Project description:Congenital hyperinsulinism (CHI), previously named persistent hyperinsulinemic hypoglycemia of infancy, is characterized by profound hypoglycemia because of excessive insulin secretion. CHI presents as two different morphological forms: a diffuse form with functional abnormality of islets throughout the pancreas and a focal form with focal islet cell adenomatous hyperplasia, which can be cured by partial pancreatectomy. Recently, we have shown that focal adenomatous hyperplasia involves the specific loss of the maternal 11p15 region and a constitutional mutation of a paternally inherited allele of the gene encoding the regulating subunit of the K(+)(ATP) channel, the sulfonylurea receptor (ABCC8 or SUR1). In the present study on a large series of 31 patients, describing both morphological features and molecular data, we report that 61% of cases (19 out of 31) carried a paternally inherited mutation not only in the ABCC8 gene as previously described but also in the second gene encoding the K(+)(ATP) channel, the inward rectifying potassium channel (KCNJ11 or KIR6.2), in 15 cases and 4 cases, respectively. Moreover our results are consistent with the presence of a duplicated paternal 11p15 allele probably because of mitotic recombination or reduplication of the paternal chromosome after somatic loss of the maternal chromosome. In agreement with the loss of the maternal chromosome, the level of expression of a maternally expressed tumor suppressor gene, H19, was greatly reduced compared to the level of expression of the paternally expressed growth promoter gene, IGF2. The expression of IGF2 was on average only moderately increased. Thus, focal forms of CHI can be considered to be a recessive somatic disease, associating an imbalance in the expression of imprinted genes in the 11p15.5 region to a somatic reduction to homozygosity of an ABCC8- or KCNJ11-recessive mutation. The former is responsible for the abnormal growth rate, as in embryonic tumors, whereas the latter leads to unregulated secretion of insulin.

Dataset Information

Update of variants identified in the pancreatic ?-cell KATP channel genes KCNJ11 and ABCC8 in individuals with congenital hyperinsulinism and diabetes.

Publications

Update of variants identified in the pancreatic β-cell K<sub>ATP</sub> channel genes KCNJ11 and ABCC8 in individuals with congenital hyperinsulinism and diabetes.

Similar Datasets

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