title: Missense mutations in the human glutathione synthetase gene result in severe metabolic acidosis, 5-oxoprolinuria, hemolytic anemia and neurological dysfunction.
abstract: Severe glutathione synthetase (GS) deficiency is a rare genetic disorder with neonatal onset. The enzymatic block of the gamma-glutamyl cycle leads to a generalized glutathione deficiency. Clinically affected patients present with severe metabolic acidosis, 5-oxoprolinuria, increased rate of hemolysis and defective function of the central nervous system. The disorder is inherited in an autosomal recessive mode and, until recently, the molecular basis has remained unknown. We have sequenced 18 GS alleles associated with enzyme deficiency and we detected missense mutations by direct sequencing of cDNAs and genomic DNA. In total, 13 different mutations were identified. Four patients were found to be compound heterozygotes and two individuals were apparently homozygous. Reduced enzymatic activities were demonstrated in recombinant protein expressed from cDNAs in four cases with different missense mutations. The results from biochemical analysis of patient specimens, supported by the properties of the expressed mutant proteins, indicate that a residual activity is present in affected individuals. Our results suggest that complete loss of function of both GS alleles is probably lethal. It is postulated that missense mutations will account for the phenotype in the majority of patients with severe GS deficiency.
authors.affiliation: Department of Clinical Genetics, Uppsala University Children's Hospital, Sweden. niklas.dahl@klingen.uu.se
authors.forename: N
authors.initials: N
authors.lastname: Dahl
authors.forename: M
authors.initials: M
authors.lastname: Pigg
authors.forename: E
authors.initials: E
authors.lastname: Ristoff
authors.forename: R
authors.initials: R
authors.lastname: Gali
authors.forename: B
authors.initials: B
authors.lastname: Carlsson
authors.forename: B
authors.initials: B
authors.lastname: Mannervik
authors.forename: A
authors.initials: A
authors.lastname: Larsson
authors.forename: P
authors.initials: P
authors.lastname: Board
mesh_terms: D000138:Acidosis / Q000235:genetics*; D000328:Adult; D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics*; D000595:Amino Acid Sequence; D000743:Anemia, Hemolytic / Q000235:genetics*; D000818:Animals; D015139:Blotting, Southern; D002675:Child, Preschool; D005981:Glutathione Synthase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D008969:Molecular Sequence Data; D009154:Mutation; D009422:Nervous System Diseases / Q000235:genetics; D010641:Phenotype; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011761:Pyrrolidonecarboxylic Acid / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015183:Restriction Mapping; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D014981:Xenopus
chemical_list: D011994:Recombinant Proteins; D005981:Glutathione Synthase; D011761:Pyrrolidonecarboxylic Acid