Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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ATP-Binding Cassette Transporters*
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Amino Acid Sequence
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Base Sequence
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Child
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DNA, Complementary / genetics
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Humans
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Hyperinsulinism / genetics*
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Hypoglycemia / genetics*
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Infant
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Molecular Sequence Data
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Nucleotides / metabolism
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Pancreas
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Point Mutation / genetics*
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Potassium Channels / chemistry
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Potassium Channels / genetics*
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Potassium Channels, Inwardly Rectifying*
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RNA Processing, Post-Transcriptional / genetics
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Receptors, Drug / chemistry
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Receptors, Drug / genetics*
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Sequence Homology, Amino Acid
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Sulfonylurea Compounds*
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Sulfonylurea Receptors
Substances
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ATP-Binding Cassette Transporters
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DNA, Complementary
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Nucleotides
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Potassium Channels
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Potassium Channels, Inwardly Rectifying
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Receptors, Drug
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Sulfonylurea Compounds
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Sulfonylurea Receptors
Associated data
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GENBANK/U63421
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GENBANK/U63422
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GENBANK/U63423
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GENBANK/U63424
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GENBANK/U63425
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GENBANK/U63441
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GENBANK/U63443
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GENBANK/U63444
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GENBANK/U63445
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GENBANK/U63446
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GENBANK/U63447
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GENBANK/U63448
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GENBANK/U63449
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GENBANK/U63450