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- Dahl, Niklas, et al.
(författare)
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Missense mutations in the human glutathione synthetase gene result in severe metabolic acidosis, 5-oxoprolinuria, hemolytic anemia and neurological dysfunction
- 1997
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 6:7, s. 1147-1152
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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- Ristoff, E, et al.
(författare)
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Inborn errors in the metabolism of glutathione
- 2007
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Ingår i: Orphanet journal of rare diseases. - : Springer Science and Business Media LLC. - 1750-1172. ; 2, s. 16-
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Tidskriftsartikel (refereegranskat)
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- Ristoff, E, et al.
(författare)
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Progressive retinal dystrophy in two sisters with glutathione synthetase (GS) deficiency
- 2007
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Ingår i: J Inherit Metab Dis. ; 30:1, s. 102-
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Tidskriftsartikel (refereegranskat)abstract
- We report the ophthalmological findings of two sisters with severe glutathione synthetase deficiency, an autosomal recessive inborn error of metabolism resulting in very low intracellular levels of the free-radical scavenger glutathione. The patients were investigated because of declining visual acuity. The most prominent finding was progressive retinal dystrophy with hyperpigmentations and maculopathy. Generally disturbed functioning of both the outer and inner layers of the retina resulted in attenuated or nearly abolished electroretinograms. These findings agree with a rod/cone type of retinal dystrophy, and we suggest that this is due to glutathione deficiency. Treatment with antioxidants such as vitamins E and C seems to prevent the progression of CNS damage. We speculate that it might also prevent retinal dystrophy in patients with glutathione synthetase deficiency. We suggest that patients with retinal dystrophy and additional neurological signs should be investigated for a defect in glutathione metabolism. Also, we recommend that patients with low levels of glutathione should be examined for retinal dystrophy. Our results suggest that a decreased capacity for scavenging reactive oxygen species and/or increased oxidative stress may cause retinal dystrophy. If this is the case, the redox state in the retina should be a potentially useful therapeutic target to prevent reduced visual function and blindness.
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