Hyperinsulinism/hyperammonemia syndrome in children with regulatory mutations in the inhibitory guanosine triphosphate-binding domain of glutamate dehydrogenase

The hyperinsulinism/hyperammonemia (HI/HA) syndrome is a form of congenital hyperinsulinism in which affected children have recurrent symptomatic hypoglycemia together with asymptomatic, persistent elevations of plasma ammonium levels. We have shown that the disorder is caused by dominant mutations...

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Bibliographic Details
Published in:The journal of clinical endocrinology and metabolism 2001-04, Vol.86 (4), p.1782-1787
Main Authors: MACMULLEN, Courtney, JIE FANG, HSU, Betty Y. L, KELLY, Andrea, DE LONLAY-DEBENEY, Pascale, SAUDUBRAY, Jean-Marie, GANGULY, Arupa, SMITH, Thomas J, STANLEY, Charles A
Format: Article
Language:English
Subjects:
Biological and medical sciences
Endocrine pancreas. Apud cells (diseases)
Endocrinopathies
Enzyme Inhibitors - metabolism
Enzyme Inhibitors - pharmacology
Exons - genetics
Female
Glutamate Dehydrogenase - analysis
Glutamate Dehydrogenase - antagonists & inhibitors
Glutamate Dehydrogenase - genetics
Guanosine Triphosphate - metabolism
Guanosine Triphosphate - pharmacology
Humans
Hyperammonemia - genetics
Hyperammonemia - physiopathology
Hyperinsulinism - genetics
Hyperinsulinism - physiopathology
Infant
Male
Medical sciences
Mutation - genetics
Polymorphism, Genetic - genetics
Polymorphism, Genetic - physiology
Protein Structure, Tertiary - genetics
Syndrome
Tumors. Hypoglycemia
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Summary:The hyperinsulinism/hyperammonemia (HI/HA) syndrome is a form of congenital hyperinsulinism in which affected children have recurrent symptomatic hypoglycemia together with asymptomatic, persistent elevations of plasma ammonium levels. We have shown that the disorder is caused by dominant mutations of the mitochondrial enzyme, glutamate dehydrogenase (GDH), that impair sensitivity to the allosteric inhibitor, GTP. In 65 HI/HA probands screened for GDH mutations, we identified 19 (29%) who had mutations in a new domain, encoded by exons 6 and 7. Six new mutations were found: Ser(217)Cys, Arg(221)Cys, Arg(265)Thr, Tyr(266)Cys, Arg(269)Cys, and Arg(269)HIS: In all five mutations tested, lymphoblast GDH showed reduced sensitivity to allosteric inhibition by GTP (IC(50), 60--250 vs. 20--50 nmol/L in normal subjects), consistent with a gain of enzyme function. Studies of ATP allosteric effects on GDH showed a triphasic response with a decrease in high affinity inhibition of enzyme activity in HI/HA lymphoblasts. All of the residues altered by exons 6 and 7 HI/HA mutations lie in the GTP-binding domain of the enzyme. These data confirm the importance of allosteric regulation of GDH as a control site for amino acid-stimulated insulin secretion and indicate that the GTP-binding site is essential for regulation of GDH activity by both GTP and ATP.
ISSN:0021-972X
1945-7197
DOI:10.1210/jc.86.4.1782