Human Molecular Genetics, Vol 6, 1147-1152, Copyright © 1997 by Oxford University Press
N Dahl, M Pigg, E Ristoff, R Gali, B Carlsson, B Mannervik, A Larsson and P Board
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.
ARTICLES
Missense mutations in the human glutathione synthetase gene result in severe metabolic acidosis, 5-oxoprolinuria, hemolytic anemia and neurological dysfunction
Department of Clinical Genetics, Uppsala University Children's Hospital, Sweden. niklas.dahl@klingen.uu.se
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