Mutation of the Pancreatic Islet Inward Rectifier Kir6.2 Also Leads to Familial Persistent Hyperinsulinemic Hypoglycemia of Infancy

• Published in: Human molecular genetics 1996-11, Vol.5 (11), p.1809-1812
• Main Authors: Thomas, Pamela, Ye, Yuyang, Lightner, Elmer
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Consanguinity; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Female; Genetic Heterogeneity; Genetic Variation - genetics; Humans; Hyperinsulinism - genetics; Hypoglycemia - genetics; Infant, Newborn; Islets of Langerhans; Male; Medical sciences; Point Mutation - genetics; Potassium Channels - genetics; Potassium Channels, Inwardly Rectifying; Tumors. Hypoglycemia
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/5.11.1809

Closure of ATP-sensitive potassium channels in pancreatic islet β-cells initiates a cascade of events that leads to insulin secretion. β-Cell ATP-sensitive potassium currents can be reconstituted by coexpression of the inward rectifier Kir6.2 and the sulfonylurea receptor (SUR), a member of the ATP-binding cassette superfamily. Mutations in SUR have been identified in individuals affected with familial persistent hyper-insulinemic hypoglycemia of infancy (PHHI), an autosomal recessive disorder of glucose metabolism which is linked to chromosome 11p15.1 and characterized by unregulated secretion of insulin and profound hypo-glycemia. Because the Kir6.2 locus is within 5 kilobases (kb) of the SUR gene on chromosome 11p15.1 and it is a necessary member of the β-cell KATP channel, we considered Kir6.2 as a candidate gene for PHHI. We identified a homozygous point mutation in Kir6.2 in the genomic DNA of a child, severely affected with PHHI, from a consanguineous family. This mutation is predicted to disrupt the conservedα-helical second transmembrane (M2) domain of the inward rectifier by substitution of a proline for a leucine residue (L147P). Mutation of Kir6.2, like SUR, appears to lead to the PHHI phenotype suggesting that Kir6.2 is necessary, although not sufficient, for normal regulation of insulin release.