ORPHA: 33574; DO: 0111681;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6p12.1 | Hemolytic anemia due to gamma-glutamylcysteine synthetase deficiency | 230450 | Autosomal recessive | 3 | GCLC | 606857 |
A number sign (#) is used with this entry because the disorder is caused by mutation in the gene encoding gamma-glutamylcysteine synthetase (GCLC; 606857), the first rate-limiting enzyme in glutathione biosynthesis.
Gamma-glutamylcysteine synthetase deficiency is 1 of 4 diseases involving enzymes in the gamma-glutamyl cycle (Meister, 1974). The other 3 disorders are glutathione synthetase deficiency (231900), 5-oxoprolinuria, which is a severe or generalized form of glutathione synthetase deficiency (266130), and gamma-glutamyl transpeptidase deficiency (231950). All except gamma-glutamyl transpeptidase deficiency are accompanied by hemolytic anemia (Larsson and Anderson, 2001).
Konrad et al. (1972) described a brother and sister of German descent with hemolytic anemia due to deficiency of the first enzyme of glutathione synthesis, gamma-glutamylcysteine synthetase. There was no known consanguinity in the family. Obligatory heterozygotes had an intermediate level of enzyme. Glutathione levels of red cells were normal in heterozygotes. Both affected sibs had late-onset spinocerebellar degeneration. The same sibs were reported by Richards et al. (1974).
Beutler et al. (1990) reported the second family in which gamma-glutamylcysteine synthetase deficiency was documented, the first family being that studied by Konrad et al. (1972) and Richards et al. (1974). The second family demonstrated that neurologic symptoms are not necessarily manifestations of this enzyme defect.
Hirono et al. (1996) described the first Japanese patients with chronic nonspherocytic hemolytic anemia and marked deficiency of red blood cell glutathione. The 3 patients were unrelated; 1 patient had decreased glutathione synthetase (601002), and the other 2 had moderate deficiency of gamma-glutamylcysteine synthetase.
Gamma-glutamylcysteine synthetase deficiency is an autosomal recessive trait. Accordingly, first-degree relatives tend to have partial reduction of the enzyme (Larsson and Anderson, 2001).
Beutler et al. (1999) determined the partial genomic structure of the catalytic subunit of GCLC. They identified a his370-to-leu mutation (606857.0001) in the GCLC gene in a patient with hemolytic anemia due to gamma-glutamylcysteine synthetase deficiency.
Using gene targeting techniques to disrupt the mouse Gclc gene, Dalton et al. (2000) observed embryonic lethality prior to embryonic day 13 (E13) in homozygous mutants. Shi et al. (2000) also reported embryonic lethality by E8.5 in mice lacking functional Gclc. Using Western immunoblot analysis, Dalton et al. (2000) detected an approximately 50% reduction in Gclc protein levels in the liver of heterozygous mutant mice, which had normal viability and fertility. They found a corresponding decrease of 45% in gamma-glutamylcysteine synthetase (Gcl) activity in heterozygous animals, but only a 20% decrease in glutathione levels. A compensatory increase of approximately 30% in hepatic ascorbate levels occurred in heterozygous animals.
Beutler, E., Gelbart, T., Kondo, T., Matsunaga, A. T. The molecular basis of a case of gamma-glutamylcysteine synthetase deficiency. Blood 94: 2890-2894, 1999. [PubMed: 10515893]
Beutler, E., Moroose, R., Kramer, L., Gelbart, T., Forman, L. Gamma-glutamylcysteine synthetase deficiency and hemolytic anemia. Blood 75: 271-273, 1990. [PubMed: 2294991]
Dalton, T. P., Dieter, M. Z., Yang, Y., Shertzer, H. G., Nebert, D. W. Knockout of the mouse glutamate cysteine ligase catalytic subunit (Gclc) gene: embryonic lethal when homozygous, and proposed model for moderate glutathione deficiency when heterozygous. Biochem. Biophys. Res. Commun. 279: 324-329, 2000. [PubMed: 11118286] [Full Text: https://doi.org/10.1006/bbrc.2000.3930]
Hirono, A., Iyori, H., Sekine, I., Ueyama, J., Chiba, H., Kanno, H., Fujii, H., Miwa, S. Three cases of hereditary nonspherocytic hemolytic anemia associated with red blood cell glutathione deficiency. Blood 87: 2071-2074, 1996. [PubMed: 8634459]
Konrad, P. N., Richards, F., Valentine, W. N., Paglia, D. E. Gamma-glutamyl-cysteine synthetase deficiency: a cause of hereditary hemolytic anemia. New Eng. J. Med. 286: 557-561, 1972. [PubMed: 5058793] [Full Text: https://doi.org/10.1056/NEJM197203162861101]
Larsson, A., Anderson, M. E. Glutathione synthetase deficiency and other disorders of the gamma-glutamyl cycle.In: Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle, D. (eds.) : The Metabolic and Molecular Bases of Inherited Disease. Vol. II. (8th ed.) New York: McGraw-Hill (pub.) 2001. Pp. 2205-2216.
Meister, A. The gamma-glutamyl cycle: diseases associated with specific enzyme deficiencies. Ann. Intern. Med. 81: 247-253, 1974. [PubMed: 4152527] [Full Text: https://doi.org/10.7326/0003-4819-81-2-247]
Richards, F., II, Cooper, M. R., Pearce, L. A., Cowan, R. J., Spurr, C. L. Familial spinocerebellar degeneration, hemolytic anemia, and glutathione deficiency. Arch. Intern. Med. 134: 534-537, 1974. [PubMed: 4852017]
Shi, Z.-Z., Osei-Frimpong, J., Kala, G., Kala, S. V., Barrios, R. J., Habib, G. M., Lukin, D. J., Danney, C. M., Matzuk, M. M., Lieberman, M. W. Glutathione synthesis is essential for mouse development but not for cell growth in culture. Proc. Nat. Acad. Sci. 10: 5101-5106, 2000.