Journal Article10.1056/NEJM199805073381904
Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene.
Charles A. Stanley,Yen K. Lieu,Betty Y.L. Hsu,Alberto Burlina,Cheryl R. Greenberg,Nancy J. Hopwood,Kusiel Perlman,Barry H. Rich,Enrico Zammarchi,Mortimer Poncz +9 more
TL;DR: The hyperinsulinism-hyperammonemia syndrome is caused by mutations in the glutamate dehydrogenase gene that impair the control of enzyme activity, consistent with overactivity of the enzyme.
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Abstract: Background A new form of congenital hyperinsulinism characterized by hypoglycemia and hyperammonemia was described recently. We hypothesized that this syndrome of hyperinsulinism and hyperammonemia was caused by excessive activity of glutamate dehydrogenase, which oxidizes glutamate to α-ketoglutarate and which is a potential regulator of insulin secretion in pancreatic beta cells and of ureagenesis in the liver. Methods We measured glutamate dehydrogenase activity in lymphoblasts from eight unrelated children with the hyperinsulinism–hyperammonemia syndrome: six with sporadic cases and two with familial cases. We identified mutations in the glutamate dehydrogenase gene by sequencing glutamate dehydrogenase complementary DNA prepared from lymphoblast messenger RNA. Site-directed mutagenesis was used to express the mutations in COS-7 cells. Results The sensitivity of glutamate dehydrogenase to inhibition by guanosine 5'-triphosphate was a quarter of the normal level in the patients with sporadic hyperinsul...
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