Mutations in the glutathione synthetase gene cause 5-oxoprolinuria

Nat Genet. 1996 Nov;14(3):361-5. doi: 10.1038/ng1196-361.


5-Oxoprolinuria (pyroglutamic aciduria) resulting from glutathione synthetase (GSS) deficiency is an inherited autosomal recessive disorder characterized, in its severe form, by massive urinary excretion of 5-oxoproline, metabolic acidosis, haemolytic anaemia and central nervous system damage. The metabolic defect results in low GSH levels presumably with feedback over-stimulation of gamma-glutamylcysteine synthesis and its subsequent conversion to 5-oxoproline. In this study, we cloned and characterized the human GSS gene and examined three families with four cases of well-documented 5-oxoprolinuria. We identified seven mutations at the GSS locus on six alleles: one splice site mutation, two deletions and four missense mutations. Bacterial expression and yeast complementation assays of the cDNAs encoded by these alleles demonstrated their functional defects. We also characterized a fifth case, an homozygous missense mutation in the gene in an individual affected by a milder-form of the GSS deficiency, which is apparently restricted to erythrocytes and only associated with haemolytic anaemia. Our data provide the first molecular genetic analysis of 5-oxoprolinuria and demonstrate that GSS deficiency with oxoprolinuria and GSS deficiency without 5-oxoprolinuria are caused by mutations in the same gene.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Metabolism, Inborn Errors / complications
  • Amino Acid Metabolism, Inborn Errors / genetics*
  • Anemia / complications
  • Anemia / genetics
  • Binding Sites
  • Erythrocytes / pathology
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Female
  • Genetic Complementation Test
  • Glutathione Synthase / genetics*
  • Glutathione Synthase / metabolism
  • Heterozygote
  • Humans
  • Male
  • Molecular Sequence Data
  • Mutation*
  • Pedigree
  • Polymerase Chain Reaction
  • Pyrrolidonecarboxylic Acid / metabolism*
  • RNA Splicing
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Schizosaccharomyces / genetics
  • Schizosaccharomyces / metabolism
  • Sequence Analysis, DNA


  • Recombinant Proteins
  • Glutathione Synthase
  • Pyrrolidonecarboxylic Acid

Associated data

  • GENBANK/U34683