title: The molecular basis of a case of gamma-glutamylcysteine synthetase deficiency.
abstract: Gamma-glutamylcysteine synthetase catalyzes the first step in glutathione synthesis. The enzyme consists of 2 subunits, heavy and light, with the heavy subunit serving as the catalytic subunit. A patient with hemolytic anemia and low red blood cell glutathione levels was found to have a deficiency of gamma-glutamylcysteine synthetase activity. Examination of cDNA from the patient and her mother showed that she was homozygous and that her mother was heterozygous for a A-->T transversion at nt1109 producing a deduced amino acid change of His370Leu. The partial genomic structure of the catalytic subunit of gamma-glutamylcysteine synthetase (GLCLC) was determined, providing some intron/exon boundaries to make it possible to sequence an affected part of the coding region from genomic DNA. The 1109A-->T mutation was not present in the DNA of 38 normal subjects. In the course of these studies we found a diallelic polymorphism in nt +206 of an intron and another polymorphism that consisted of a duplication of a CAGC at cDNA nt1972-1975 in the 3' untranslated region. The 2 polymorphisms were found to be only in partial linkage disequilibrium.
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: E
authors.initials: E
authors.lastname: Beutler
authors.forename: T
authors.initials: T
authors.lastname: Gelbart
authors.forename: T
authors.initials: T
authors.lastname: Kondo
authors.forename: A T
authors.initials: AT
authors.lastname: Matsunaga
mesh_terms: D000293:Adolescent; D000592:Amino Acid Metabolism, Inborn Errors / Q000097:blood / Q000235:genetics*; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000743:Anemia, Hemolytic / Q000097:blood / Q000201:enzymology / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D020134:Catalytic Domain / Q000235:genetics; D003062:Codon / Q000235:genetics; D003241:Consanguinity; D017931:DNA Primers; D018076:DNA, Complementary / Q000235:genetics; D004912:Erythrocytes / Q000201:enzymology; D005260:Female; D005796:Genes; D005721:Glutamate-Cysteine Ligase / Q000172:deficiency / Q000235:genetics*; D005978:Glutathione / Q000172:deficiency; D006720:Homozygote; D006801:Humans; D007859:Learning Disabilities / Q000097:blood / Q000201:enzymology / Q000235:genetics*; D008214:Lymphocytes / Q000737:chemistry; D051379:Mice; D008969:Molecular Sequence Data; D017354:Point Mutation; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013045:Species Specificity; D014162:Transfection
chemical_list: D003062:Codon; D017931:DNA Primers; D018076:DNA, Complementary; D011993:Recombinant Fusion Proteins; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione