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Hyperinsulinism/Hyperammonemia Syndrome in Children with Regulatory Mutations in the Inhibitory Guanosine Triphosphate-Binding Domain of Glutamate Dehydrogenase¹

Division of Endocrinology, The Children’s Hospital of Philadelphia (C.M., J.F., B.Y.L.H., A.K., C.A.S.), and Departments of Pediatrics and Genetics (A.G.), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104; Department of Pediatrics, Hopital des Enfants-Malades (P.d.L.-D., J.-M.S.), 75743 Paris CEDEX 15, France; and Department of Biological Sciences, Purdue University (T.A.S.), West Lafayette, Indiana 47907

Address all correspondence and requests for reprints to: Charles A. Stanley, M.D., Division of Endocrinology, The Children’s Hospital of Philadelphia, 3516 Civic Center Boulevard, Philadelphia, Pennsylvania 19104. E-mail: stanleyc{at}email.chop.edu

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: 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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