title: Spectrum of glutamate dehydrogenase mutations in Japanese patients with congenital hyperinsulinism and hyperammonemia syndrome.
abstract: BACKGROUND
  Congenital hyperinsulinism and hyperammonemia (CHH) is caused by gain of function of glutamate dehydrogenase (GDH). The genetic abnormalities are known to be located in three specific regions on the GDH protein. We describe here three different missense mutations identified in five new Japanese patients with CHH. And to study the genotype-phenotype correlations in patients with GLUD1 mutations, we analyzed previously reported Japanese cases.
  
  
  METHODS
  An Epstein-Barr virus-transformed lymphoblastoid cell line was established from the 5 patients and control subjects, and was used for enzymatic and molecular analyses.
  
  
  RESULTS
  All patients developed seizures with loss of consciousness associated with hypoglycemia and had persistent hyperammonemia. All patients had similar basal GDH activity of lymphoblasts and insensitivity to GTP inhibition. Genetic studies identified heterozygous I444M mutation in Patient 11, S217C mutation in Patient 1, and H262Y mutation in Patients 2, 3, and 4. Patients 3 and 4 were child and father, respectively. COS cell expression study confirmed that I444M and H262Y mutations were disease-causing genes.
  
  
  CONCLUSIONS
  We identified three mutations (I444M, H262Y, and S217C), and the former is a newly described mutation. A summary of 17 reported Japanese patients (10 boys and 7 girls) with GDH mutations showed 8 patients had mutation at the site of the GTP-binding region, 2 at the site of the antenna-like structure, and 7 at the site of the hinge region. Analysis of the reported cases showed no clear association between clinical phenotype and mutation sites. However, G446D mutation seems to be associated with serious abnormalities.
authors: Department of Pediatrics, Osaka City University, Graduate School of Medicine, Japan.
authors: Kazuyoshi
authors: K
authors: Aso
authors: Yoshiyuki
authors: Y
authors: Okano
authors: Taisuke
authors: T
authors: Takeda
authors: Osamu
authors: O
authors: Sakamoto
authors: Kyoko
authors: K
authors: Ban
authors: Kazumi
authors: K
authors: Iida
authors: Tsunekazu
authors: T
authors: Yamano
authors: Haruo
authors: H
authors: Shintaku
mesh_terms: D000293:Adolescent; D000818:Animals; D019556:COS Cells; D002461:Cell Line, Transformed; D002648:Child; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D005969:Glutamate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006946:Hyperinsulinism / Q000150:complications / Q000201:enzymology / Q000235:genetics*; D007003:Hypoglycemia / Q000150:complications / Q000201:enzymology / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D007564:Japan; D008297:Male; D020125:Mutation, Missense; D010641:Phenotype; D012640:Seizures / Q000201:enzymology / Q000235:genetics; D014162:Transfection; D014474:Unconsciousness / Q000201:enzymology / Q000235:genetics
chemical_list: D005969:Glutamate Dehydrogenase; C561840:GLUD1 protein, human