INACTIVATION OF THE FIRST NUCLEOTIDE-BINDING FOLD OF THE SULFONYLUREARECEPTOR, AND FAMILIAL PERSISTENT HYPERINSULINEMIC HYPOGLYCEMIA OF INFANCY

Familial persistent hyperinsulinemic hypoglycemia of infancy is a diso rder of glucose homeostasis and is characterized by unregulated insuli n secretion and profound hypoglycemia. Loss-of-function mutations in t he second nucleotide-binding fold of the sulfonylurea receptor, a subu nit of the pancreatic-islet beta-cell ATP-dependent potassium channel, has been demonstrated to be causative for persistent hyperinsulinemic hypoglycemia of infancy. We now describe three additional mutations i n the first nucleotide-binding fold of the sulfonylurea-receptor gene. One point mutation disrupts the highly conserved Walker A motif of th e first nucleotide-binding-fold region. The other two mutations occur in noncoding sequences required for RNA processing and are predicted t o disrupt the normal splicing pathway of the sulfonylurea-receptor mRN A precursor. These data suggest that both nucleotide-binding-fold regi ons of the sulfonylurea receptor are required for normal regulation of beta-cell ATP-dependent potassium channel activity and insulin secret ion.