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Previous Volume 338:1352-1357 May 7, 1998 Number 19 Next

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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 -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 hyperinsulinism–hyperammonemia syndrome and half the normal level in patients with familial cases and their affected relatives, findings consistent with overactivity of the enzyme. These differences in enzyme insensitivity correlated with differences in the severity of hypoglycemia in the two groups. All eight children were heterozygous for the wild-type allele and had a mutation in the proposed allosteric domain of the enzyme. Four different mutations were identified in the six patients with sporadic cases; the two patients with familial cases shared a fifth mutation. In two clones of COS-7 cells transfected with the mutant sequence from one patient, the sensitivity of the enzyme to guanosine 5'-triphosphate was reduced, findings similar to those in the child's lymphoblasts.

Conclusions The hyperinsulinism–hyperammonemia syndrome is caused by mutations in the glutamate dehydrogenase gene that impair the control of enzyme activity.

Source Information

From the Divisions of Endocrinology (C.A.S., Y.K.L., B.Y.L.H.) and Hematology (M.P.), Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia; the Department of Pediatrics, University of Padua, Padua, Italy (A.B.B.); the Section of Genetics and Metabolism, Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Canada (C.R.G.); the Endocrinology Division, C.S. Mott Children's Hospital, University of Michigan School of Medicine, Ann Arbor (N.J.H.); the Division of Endocrinology, Hospital for Sick Children, University of Toronto School of Medicine, Toronto (K.P.); the Section of Endocrinology, Chicago Children's Hospital, University of Chicago Pritzker School of Medicine, Chicago (B.H.R.); and the Department of Pediatrics, University of Florence, Florence, Italy (E.Z.).

Address reprint requests to Dr. Stanley at the Division of Endocrinology, Children's Hospital of Philadelphia, 34th St. and Civic Center Blvd., Philadelphia, PA 19104.

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