Novel dominant K_(ATP) channel mutations in infants with congenital hyperinsulinism: Validation by in vitro expression studies and in vivo carrier phenotyping

摘要

Inactivating mutations in the genes encoding the two subunits of the pancreatic beta-cell K_(ATP) channel, ABCC8 and KCNJ11, are the most common finding in children with congenital hyperinsulinism (HI). Interpreting novel missense variants in these genes is problematic, because they can be either dominant or recessive mutations, benign polymorphisms, or diabetes mutations. This report describes six novel missense variants in ABCC8 and KCNJ11 that were identified in 11 probands with congenital HI. One of the three ABCC8 mutations (p.Alal458Thr) and all three KCNJ11 mutations were associated with responsiveness to diazoxide. Sixteen family members carried the ABCC8 or KCNJ11 mutations; only two had hypoglycemia detected at birth and four others reported symptoms of hypoglycemia. Phenotype testing of seven adult mutation carriers revealed abnormal protein-induced hypoglycemia in all; fasting hypoketotic hypoglycemia was demonstrated in four of the seven. All of six mutations were confirmed to cause dominant pathogenic defects based on in vitro expression studies in C0Sm6 cells demonstrating normal trafficking, but reduced responses to MgADP and diazoxide. These results indicate a combination of in vitro and in vivo phenotype tests can be used to differentiate dominant from recessive K_(ATP) channel HI mutations and personalize management of children with congenital HI.