Mutations in the glutathione synthetase gene cause 5-oxoprolinuria.
Nat Genet
; 14(3): 361-5, 1996 Nov.
Article
in En
| MEDLINE
| ID: mdl-8896573
ABSTRACT
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.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pyrrolidonecarboxylic Acid
/
Amino Acid Metabolism, Inborn Errors
/
Glutathione Synthase
/
Mutation
Limits:
Female
/
Humans
/
Male
Language:
En
Journal:
Nat Genet
Journal subject:
GENETICA MEDICA
Year:
1996
Document type:
Article
Affiliation country: