Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene
Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene
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DOI：
10.1056/nejm199805073381904
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发表时间：
1998-05-07
影响因子：
158.5
通讯作者：
Poncz, M
中科院分区：
文献类型：
--
作者：
Stanley, CA;Lieu, YK;Poncz, M
背景近年来发现一种以低血糖和高血氨为特征的先天性高胰岛素血症。我们假设这种高胰岛素血症和高氨血症综合征是由谷氨酸脱氢酶的过度活性引起的，谷氨酸脱氢酶将谷氨酸氧化为α-酮戊二酸，并且是胰腺β细胞中胰岛素分泌和肝脏中尿素生成的潜在调节剂。6例为散发病例，2例为家族性病例。我们通过对从淋巴母细胞信使RNA中制备的谷氨酸脱氢酶互补DNA进行测序，鉴定了谷氨酸脱氢酶基因的突变。结果散发性高胰岛素血症-高氨血症综合征患者谷氨酸脱氢酶对5 '-三磷酸鸟苷抑制的敏感性为正常水平的1/4，而家族性高胰岛素血症患者及其亲属谷氨酸脱氢酶的敏感性为正常水平的1/2，与谷氨酸脱氢酶的过度活性一致。酶不敏感性的这些差异与两组中低血糖严重程度的差异相关。所有8名儿童均为野生型等位基因杂合子，并且在该酶的拟议变构域中存在突变。在6例散发病例中发现了4种不同的突变; 2例熟悉病例中发现了第5种突变。在两个克隆的COS-7细胞转染的突变序列从一个病人，酶的敏感性鸟苷5 '-三磷酸减少，发现类似于那些在孩子的lymphoblasts.Conclusions的高胰岛素血症高氨血症综合征是由谷氨酸脱氢酶基因的突变，损害酶活性的控制。（C）1998年，马萨诸塞州医学会。
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 alpha-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 familiar 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 familiar 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. (C)1998, Massachusetts Medical Society.