In a 16-year-old French girl with transient neonatal diabetes mellitus (610374) who had a recurrence of diabetes at age 11 and in affected members of an unrelated 5-generation French family with transient neonatal diabetes and adult-onset type II diabetes mellitus (125853), Babenko et al. (2006) identified heterozygosity for an arg1379-to-cys (R1379C) substitution. The mutation arose de novo in the first patient. The 5-year-old female proband of the family had transient neonatal diabetes. Her father developed diabetes at age 32 that was treated with sulfonylureas, and her paternal grandmother was diagnosed with gestational diabetes and treated with diet, and a paternal great-aunt was diagnosed at age 44 with diabetes that was also treated with sulfonylureas. Babenko et al. (2006) proposed that mutations of the ABCC8 gene might give rise to a monogenic form of type II diabetes with variable expression and age at onset.
De Wet et al. (2007) performed functional studies of this mutation, which they designated R1380C, and demonstrated enhanced MgATP hydrolysis by purified isolated fusion proteins of maltose-binding protein and the second nucleotide-binding domain of ABCC8, in which the mutation is located. This increase in ATPase activity reduced the sensitivity of the channel to inhibition by MgATP and increased the whole-cell K(ATP) current. The authors noted that in pancreatic beta cells, such an increase in K(ATP) current would be expected to impair insulin secretion and thereby cause diabetes.
