title: Molecular basis of glutathione reductase deficiency in human blood cells.
abstract: Hereditary glutathione reductase (GR) deficiency was found in only 2 cases when testing more than 15 000 blood samples. We have investigated the blood cells of 2 patients (1a and 1b) in a previously described family suffering from favism and cataract and of a novel patient (2) presenting with severe neonatal jaundice. Red blood cells and leukocytes of the patients in family 1 did not contain any GR activity, and the GR protein was undetectable by Western blotting. Owing to a 2246-bp deletion in the patients' DNA, translated GR is expected to lack almost the complete dimerization domain, which results in unstable and inactive enzyme. The red blood cells from patient 2 did not exhibit GR activity either, but the patient's leukocytes contained some residual activity that correlated with a weak protein expression. Patient 2 was found to be a compound heterozygote, with a premature stop codon on one allele and a substitution of glycine 330, a highly conserved residue in the superfamily of NAD(P)H-dependent disulfide reductases, into alanine on the other allele. Studies on recombinant GR G330A revealed a drastically impaired thermostability of the protein. This is the first identification of mutations in the GR gene causing clinical GR deficiency.
authors.affiliation: Sanquin Research and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Plesmanlaan 125, 1066 CX Amsterdam, the Netherlands.
authors.forename: Nanne M
authors.initials: NM
authors.lastname: Kamerbeek
authors.forename: Rob
authors.initials: R
authors.lastname: van Zwieten
authors.forename: Martin
authors.initials: M
authors.lastname: de Boer
authors.forename: Gert
authors.initials: G
authors.lastname: Morren
authors.forename: Herma
authors.initials: H
authors.lastname: Vuil
authors.forename: Natalja
authors.initials: N
authors.lastname: Bannink
authors.forename: Carsten
authors.initials: C
authors.lastname: Lincke
authors.forename: Koert M
authors.initials: KM
authors.lastname: Dolman
authors.forename: Katja
authors.initials: K
authors.lastname: Becker
authors.forename: R Heiner
authors.initials: RH
authors.lastname: Schirmer
authors.forename: Stephan
authors.initials: S
authors.lastname: Gromer
authors.forename: Dirk
authors.initials: D
authors.lastname: Roos
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D002386:Cataract / Q000201:enzymology / Q000235:genetics*; D002675:Child, Preschool; D018389:Codon, Nonsense / Q000235:genetics; D004912:Erythrocytes / Q000201:enzymology; D005236:Favism / Q000201:enzymology / Q000235:genetics*; D005260:Female; D030342:Genetic Diseases, Inborn / Q000201:enzymology / Q000235:genetics*; D005980:Glutathione Reductase / Q000737:chemistry / Q000172:deficiency*; D006579:Heterozygote; D006801:Humans; D007231:Infant, Newborn; D007567:Jaundice, Neonatal / Q000201:enzymology / Q000235:genetics*; D007962:Leukocytes / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D017384:Sequence Deletion
chemical_list: D018389:Codon, Nonsense; D005980:Glutathione Reductase