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

Courtney Macmullen, Jie Fang, Betty Y L Hsu, Andrea Kelly, Pascale De Lonlay-Debeney, Jean Marie Saudubray, Arupa Ganguly, Thomas Smith, Charles A. Stanley, Rosalind Brown, Neil Buist, Majed Dasouki, Richard Fefferman, Dorothy Grange, Lefkothea Karaviti, Christina Luedke, Barbara Marriage, Judith McLaughlin, Kusiel Perlman, Margretta Seashore & 1 others Guy Van Vliet

Research output: Contribution to journalArticle

124 Citations (Scopus)

Abstract

The hyperinsulinism/hyperammonemia (HI/HA) syndrome is a form of congenital hyperinsulinism in which affected children have recurrent symptomatic hypoglycemia together with asymptematic, 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: Ser217Cys, Arg221Cys, Arg265Thr, Tyr266Cys, Arg269Cys, and Arg269His. In all five mutations tested, lymphoblast GDH showed reduced sensitivity to allosteric inhibition by GTP (IC50, 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.

Original languageEnglish (US)
Pages (from-to)1782-1787
Number of pages6
JournalJournal of Clinical Endocrinology and Metabolism
Volume86
Issue number4
DOIs
StatePublished - 2001
Externally publishedYes

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Glutamate Dehydrogenase
Guanosine Triphosphate
Hyperammonemia
Mutation
Hyperinsulinism
Enzymes
Exons
Congenital Hyperinsulinism
Adenosine Triphosphate
Allosteric Regulation
Enzyme inhibition
Enzyme activity
Ammonium Compounds
Hypoglycemia
Inhibitory Concentration 50
Hyperinsulinemic hypoglycemia, familial, 6
Binding Sites
Insulin
Plasmas
Amino Acids

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

Cite this

Hyperinsulinism/hyperammonemia syndrome in children with regulatory mutations in the inhibitory guanosine triphosphate-binding domain of glutamate dehydrogenase. / Macmullen, Courtney; Fang, Jie; Hsu, Betty Y L; Kelly, Andrea; De Lonlay-Debeney, Pascale; Saudubray, Jean Marie; Ganguly, Arupa; Smith, Thomas; Stanley, Charles A.; Brown, Rosalind; Buist, Neil; Dasouki, Majed; Fefferman, Richard; Grange, Dorothy; Karaviti, Lefkothea; Luedke, Christina; Marriage, Barbara; McLaughlin, Judith; Perlman, Kusiel; Seashore, Margretta; Van Vliet, Guy.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 86, No. 4, 2001, p. 1782-1787.

Research output: Contribution to journalArticle

Macmullen, C, Fang, J, Hsu, BYL, Kelly, A, De Lonlay-Debeney, P, Saudubray, JM, Ganguly, A, Smith, T, Stanley, CA, Brown, R, Buist, N, Dasouki, M, Fefferman, R, Grange, D, Karaviti, L, Luedke, C, Marriage, B, McLaughlin, J, Perlman, K, Seashore, M & Van Vliet, G 2001, 'Hyperinsulinism/hyperammonemia syndrome in children with regulatory mutations in the inhibitory guanosine triphosphate-binding domain of glutamate dehydrogenase', Journal of Clinical Endocrinology and Metabolism, vol. 86, no. 4, pp. 1782-1787. https://doi.org/10.1210/jc.86.4.1782
Macmullen, Courtney ; Fang, Jie ; Hsu, Betty Y L ; Kelly, Andrea ; De Lonlay-Debeney, Pascale ; Saudubray, Jean Marie ; Ganguly, Arupa ; Smith, Thomas ; Stanley, Charles A. ; Brown, Rosalind ; Buist, Neil ; Dasouki, Majed ; Fefferman, Richard ; Grange, Dorothy ; Karaviti, Lefkothea ; Luedke, Christina ; Marriage, Barbara ; McLaughlin, Judith ; Perlman, Kusiel ; Seashore, Margretta ; Van Vliet, Guy. / Hyperinsulinism/hyperammonemia syndrome in children with regulatory mutations in the inhibitory guanosine triphosphate-binding domain of glutamate dehydrogenase. In: Journal of Clinical Endocrinology and Metabolism. 2001 ; Vol. 86, No. 4. pp. 1782-1787.
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abstract = "The hyperinsulinism/hyperammonemia (HI/HA) syndrome is a form of congenital hyperinsulinism in which affected children have recurrent symptomatic hypoglycemia together with asymptematic, 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: Ser217Cys, Arg221Cys, Arg265Thr, Tyr266Cys, Arg269Cys, and Arg269His. In all five mutations tested, lymphoblast GDH showed reduced sensitivity to allosteric inhibition by GTP (IC50, 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.",
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AU - Macmullen, Courtney

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AU - Hsu, Betty Y L

AU - Kelly, Andrea

AU - De Lonlay-Debeney, Pascale

AU - Saudubray, Jean Marie

AU - Ganguly, Arupa

AU - Smith, Thomas

AU - Stanley, Charles A.

AU - Brown, Rosalind

AU - Buist, Neil

AU - Dasouki, Majed

AU - Fefferman, Richard

AU - Grange, Dorothy

AU - Karaviti, Lefkothea

AU - Luedke, Christina

AU - Marriage, Barbara

AU - McLaughlin, Judith

AU - Perlman, Kusiel

AU - Seashore, Margretta

AU - Van Vliet, Guy

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N2 - The hyperinsulinism/hyperammonemia (HI/HA) syndrome is a form of congenital hyperinsulinism in which affected children have recurrent symptomatic hypoglycemia together with asymptematic, 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: Ser217Cys, Arg221Cys, Arg265Thr, Tyr266Cys, Arg269Cys, and Arg269His. In all five mutations tested, lymphoblast GDH showed reduced sensitivity to allosteric inhibition by GTP (IC50, 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.

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