Inactivation of the first nucleotide-binding fold of the sulfonylurea receptor, and familial persistent hyperinsulinemic hypoglycemia of infancy.
Familial persistent hyperinsulinemic hypoglycemia of infancy is a disorder of glucose homeostasis and is characterized by unregulated insulin secretion and profound hypoglycemia. Loss-of-function mutations in the second nucleotide-binding fold of the sulfonylurea receptor, a subunit 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 in the first nucleotide-binding fold of the sulfonylurea-receptor gene. One point mutation disrupts the highly conserved Walker A motif of the first nucleotide-binding-fold region. The other two mutations occur in noncoding sequences required for RNA processing and are predicted to disrupt the normal splicing pathway of the sulfonylurea-receptor mRNA precursor. These data suggest that both nucleotide-binding-fold regions of the sulfonylurea receptor are required for normal regulation of beta-cell ATP-dependent potassium channel activity and insulin secretion.
Thomas
P M
PM
Department of Medical Specialties, University of Texas M. D. Anderson Cancer Center, Houston, USA. pamt@umich.edu
Wohllk
N
N
Huang
E
E
Kuhnle
U
U
Rabl
W
W
Gagel
R F
RF
Cote
G J
GJ
D018528:ATP-Binding Cassette Transporters; D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D018076:DNA, Complementary / Q000235:genetics; D006801:Humans; D006946:Hyperinsulinism / Q000235:genetics*; D007003:Hypoglycemia / Q000235:genetics*; D007223:Infant; D008969:Molecular Sequence Data; D009711:Nucleotides / Q000378:metabolism; D010179:Pancreas; D017354:Point Mutation / Q000235:genetics*; D015221:Potassium Channels / Q000737:chemistry / Q000235:genetics*; D024661:Potassium Channels, Inwardly Rectifying; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics; D011955:Receptors, Drug / Q000737:chemistry / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D013453:Sulfonylurea Compounds; D064233:Sulfonylurea Receptors
D018528:ATP-Binding Cassette Transporters; D018076:DNA, Complementary; D009711:Nucleotides; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D013453:Sulfonylurea Compounds; D064233:Sulfonylurea Receptors