Alternative titles; symbols
HGNC Approved Gene Symbol: GSS
SNOMEDCT: 124706000, 234589002, 39112005;
Cytogenetic location: 20q11.22 Genomic coordinates (GRCh38): 20:34,928,432-34,956,027 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20q11.22 | Glutathione synthetase deficiency | 266130 | Autosomal recessive | 3 |
| Hemolytic anemia due to glutathione synthetase deficiency | 231900 | Autosomal recessive | 3 |
Glutathione (GSH), a ubiquitous low molecular mass thiol, is important for a variety of biologic functions, including protection of cells from oxidative damage by free radicals, detoxification of xenobiotics, and membrane transport (Meister and Anderson, 1983; Uhlig and Wendel, 1992). The consecutive actions of gamma-glutamylcysteine synthetase (606857) and glutathione synthetase produce GSH from the amino acids cysteine, glutamate, and glycine.
Shi et al. (1996) cloned and characterized the human GSS gene.
Webb et al. (1995) found by Southern blots hybridized with a glutathione synthetase cDNA that there appears to be a single glutathione synthetase gene (GSS) in the human genome. Analysis of somatic cell hybrids showed that GSS is located on chromosome 20, and this assignment was refined to 20q11.2 by fluorescence in situ hybridization.
Shi et al. (1996) performed a mutation search of the GSS gene in 3 families with glutathione synthetase deficiency (GSSD; 266130), or 5-oxoprolinuria, an autosomal recessive disorder characterized, in its severe form, by massive urinary excretion of 5-oxoproline, metabolic acidosis, hemolytic anemia, and central nervous system damage. They identified 7 mutations at the GSS locus on 6 alleles: 1 splice site mutation, 2 deletions, and 4 missense mutations (601002.0001-601002.0006). Bacterial expression and yeast complementation assays of the cDNAs encoded by these alleles demonstrated their functional defects. They also identified a homozygous missense mutation in the GSS gene (601002.0007) in an individual affected by the milder form of GSS deficiency, which is apparently restricted to erythrocytes and only associated with hemolytic anemia (GSSDE; 231900).
Dahl et al. (1997) identified a total of 13 different mutations in the GSS gene in 9 patients with severe glutathione synthetase deficiency. The patients were all unrelated and came from different geographic areas. All patients had presented with metabolic acidosis, hemolytic anemia, and 5-oxoprolinuria; however, neurologic symptoms were variable. Among the 13 different missense mutations involved, 2 were found in patients presenting with functional impairment of the central nervous system. One of these, aged 22 years at last examination, had a low normal IQ and abnormal retinogram. Four patients were found to be compound heterozygotes and 2 were apparently homozygous. Reduced enzyme activities were demonstrated in recombinant protein expressed from cDNAs in 4 cases with different missense mutations. The results from biochemical analysis of patient specimens, supported by the properties of the expressed mutant proteins, indicated that residual activity was present in affected individuals. Dahl et al. (1997) suggested that complete loss of function of both glutathione synthetase alleles is probably lethal. They postulated that missense mutations will account for the phenotype in most patients with severe GS deficiency.
In 41 patients (33 previously reported) with glutathione synthetase deficiency from 33 families, Njalsson et al. (2005) evaluated genotype, enzyme activity, metabolite levels, and clinical phenotype. They identified 27 different mutations; 23 patients were homozygotes and 18 were compound heterozygotes. The moderate and severe clinical phenotypes could not be distinguished based on enzyme activity or glutathione or gamma-glutamylcysteine levels in cultured fibroblasts. All mutations causing frameshifts, premature stop codons, or aberrant splicing were associated with moderate or severe clinical phenotypes. Njalsson et al. (2005) concluded that additional genetic or environmental factors modify at least the moderate and severe phenotypes and that the clinical classification given to patients may be influenced by variation in follow-up.
In a family in which 2 brothers exhibited 5-oxoprolinuria (GSSD; 266130), metabolic acidosis, hemolytic anemia, and mental retardation, Shi et al. (1996) found compound heterozygosity for mutations in the GSS gene: a G-to-A transition at the end of exon 4 (position 491) of the cDNA, which may cause an RNA splicing error or a missense mutation (arg164-to-gln); and, in exon 1, a deletion of G corresponding to nucleotide 3 or 4 in the cDNA sequence (+1ATGGCC...), predicting a frameshift and/or abolition of the translation initiation site. These 2 changes were designated as 491G-A and 3(4)delG, respectively.
For discussion of the 1-bp deletion in the GSS gene (3(4)delG) that was found in compound heterozygous state in 2 brothers with 5-oxoprolinuria (GSSD; 266130) by Shi et al. (1996), see 601002.0001.
In a patient with 5-oxoprolinuria (GSSD; 266130), Shi et al. (1996) found compound heterozygosity for 2 C-to-T transitions at nucleotides 799 and 847 in the GSS gene, implying 2 missense mutations: arg267 to trp (R267W) and arg283 to cys (R283C; 601002.0004) in exons 8 and 9, respectively.
For discussion of the arg283-to-cys (R283C) mutation in the GSS gene that was found in compound heterozygous state in a patient with 5-oxoprolinuria (GSSD; 266130) by Shi et al. (1996), see 601002.0003.
In a patient with 5-oxoprolinuria (GSSD; 266130), Shi et al. (1996) found 3 sequence alterations: 2 missense mutations (373C-T, leading to arg125 to cys, and 941C-T, leading to pro314 to leu) and a 6-bp in-frame deletion (1137del6, resulting in the deletion of val380 and gln381) in exons 4, 9, and 11, respectively. The R125C mutation was transmitted from the father; the other 2 mutations came from the mother, indicating that they are on the same allele (601002.0006). In an in vitro expression system, the mutant cDNAs corresponding to the 2 alleles from this family failed to complement and produced proteins with undetectable activity (373C-T) or altered solubility (doubly mutant allele).
For discussion of the in cis pro314-to-leu (P314L) substitution and the 6-bp deletion (1137del6) that were found in compound heterozygous state with an R125C substitution in the GSS gene in a patient with 5-oxoprolinuria (GSSD; 266130) by Shi et al. (1996), see 601002.0005.
In a patient with GSS deficiency restricted to erythrocytes and associated only with hemolytic anemia (GSSDE; 231900) (Mohler et al., 1970), Shi et al. (1996) found homozygosity for a 656A-G transition that resulted in and asp219-to-gly (D219G) substitution. Although the patient's parents were not related, they were both of Scottish descent, and the families had lived in the same county for several generations. The allele was responsible for reduced activity and instability of the expressed protein, but was more active than the other 6 alleles that were found by Shi et al. (1996) to result in 5-oxoprolinuria.
Vives Corrons et al. (2001) found homozygosity for the D219G mutation in 2 unrelated Spanish adults with a well-compensated hemolytic syndrome without anemia or splenomegaly at steady state. One of these patients was diagnosed after an episode of acute hemolytic anemia following fava bean ingestion.
Dahl, N., Pigg, M., Ristoff, E., Gali, R., Carlsson, B., Mannervik, B., Larsson, A., Board, P. Missense mutations in the human glutathione synthetase gene result in severe metabolic acidosis, 5-oxoprolinuria, hemolytic anemia and neurological dysfunction. Hum. Molec. Genet. 6: 1147-1152, 1997. [PubMed: 9215686] [Full Text: https://doi.org/10.1093/hmg/6.7.1147]
Meister, A., Anderson, M. E. Glutathione. Annu. Rev. Biochem. 52: 711-760, 1983. [PubMed: 6137189] [Full Text: https://doi.org/10.1146/annurev.bi.52.070183.003431]
Mohler, D. N., Majerus, P. W., Minnich, V., Hess, C. E., Garrick, M. D. Glutathione synthetase deficiency as a cause of hereditary hemolytic disease. New Eng. J. Med. 283: 1253-1257, 1970. [PubMed: 5476481] [Full Text: https://doi.org/10.1056/NEJM197012032832304]
Njalsson, R., Ristoff, E., Carlsson, K., Winkler, A., Larsson, A., Norgren, S. Genotype, enzyme activity, glutathione level, and clinical phenotype in patients with glutathione synthetase deficiency. Hum. Genet. 116: 384-389, 2005. [PubMed: 15717202] [Full Text: https://doi.org/10.1007/s00439-005-1255-6]
Shi, Z.-Z., Habib, G. M., Rhead, W. J., Gahl, W. A., He, X., Sazer, S., Lieberman, M. W. Mutations in the glutathione synthetase gene cause 5-oxoprolinuria. Nature Genet. 14: 361-365, 1996. [PubMed: 8896573] [Full Text: https://doi.org/10.1038/ng1196-361]
Uhlig, S., Wendel, A. The physiological consequences of glutathione variations. Life Sci. 51: 1083-1094, 1992. [PubMed: 1518371] [Full Text: https://doi.org/10.1016/0024-3205(92)90509-n]
Vives Corrons, J.-L., Alvarez, R., Pujades, A., Zarza, R., Oliva, E., Lasheras, G., Callis, M., Ribes, A., Gelbart, T., Beutler, E. Hereditary non-spherocytic haemolytic anaemia due to red blood cell glutathione synthetase deficiency in four unrelated patients from Spain: clinical and molecular studies. Brit. J. Haemat. 112: 475-482, 2001. [PubMed: 11167850] [Full Text: https://doi.org/10.1046/j.1365-2141.2001.02526.x]
Webb, G. C., Vaska, V. L., Gali, R. R., Ford, J. H., Board, P. G. The gene encoding human glutathione synthetase (GSS) maps to the long arm of chromosome 20 at band 11.2. Genomics 30: 617-619, 1995. [PubMed: 8825653] [Full Text: https://doi.org/10.1006/geno.1995.1287]