Mutations in the glutathione synthetase gene cause 5-oxoprolinuria.
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.
Shi
Z Z
ZZ
Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, USA.
Habib
G M
GM
Rhead
W J
WJ
Gahl
W A
WA
He
X
X
Sazer
S
S
Lieberman
M W
MW
D000592:Amino Acid Metabolism, Inborn Errors / Q000150:complications / Q000235:genetics*; D000740:Anemia / Q000150:complications / Q000235:genetics; D001665:Binding Sites; D004912:Erythrocytes / Q000473:pathology; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D005260:Female; D005816:Genetic Complementation Test; D005981:Glutathione Synthase / Q000235:genetics* / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011761:Pyrrolidonecarboxylic Acid / Q000378:metabolism*; D012326:RNA Splicing; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012568:Schizosaccharomyces / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA
D011994:Recombinant Proteins; D005981:Glutathione Synthase; D011761:Pyrrolidonecarboxylic Acid