TY - JOUR
T1 - Hyperinsulinism/hyperammonemia syndrome in children with regulatory mutations in the inhibitory guanosine triphosphate-binding domain of glutamate dehydrogenase
AU - Macmullen, Courtney
AU - Fang, Jie
AU - Hsu, Betty Y.L.
AU - Kelly, Andrea
AU - De Lonlay-Debeney, Pascale
AU - Saudubray, Jean Marie
AU - Ganguly, Arupa
AU - Smith, Thomas J.
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
PY - 2001
Y1 - 2001
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.
AB - 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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U2 - 10.1210/jc.86.4.1782
DO - 10.1210/jc.86.4.1782
M3 - Article
C2 - 11297618
AN - SCOPUS:0035030231
SN - 0021-972X
VL - 86
SP - 1782
EP - 1787
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 4
ER -