Mutations in the glutathione synthetase gene cause 5-oxoprolinuria

5-Oxoprolinuria (pyroglutamic aciduria)1,2 resulting from glutathione synthetase (GSS) deficiency3,4 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 γ-glutamylcysteine synthesis and its subsequent conversion to 5-oxoproline3,4. In this study, we cloned and characterized the human GSS gene and examined three families with four cases of well-documented 5-oxoprolinuria5,6. 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 mis-sense mutation in the gene in an individual affected by a milder-form of the GSS deficiency7, 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. © 1996 Nature Publishing Group.