Alternative titles; symbols
HGNC Approved Gene Symbol: GCLM
Cytogenetic location: 1p22.1 Genomic coordinates (GRCh38): 1:93,885,199-93,909,430 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p22.1 | {Myocardial infarction, susceptibility to} | 608446 | 3 |
Gamma-glutamylcysteine synthetase, also known as glutamate-cysteine ligase (EC 6.3.2.2), is the first rate-limiting enzyme in glutathione biosynthesis.
Human liver gamma-glutamylcysteine synthetase consists of 2 subunits: a heavy catalytic subunit (GCLC; 606857) and a light regulatory subunit. Gipp et al. (1995) reported the cloning of a full-length cDNA for the light subunit. The cDNA encodes a 274-amino acid protein of approximately 30.7 kD that is 96% identical to the previously cloned rat sequence (Huang et al., 1993). Northern blot analysis detected 1.4- and 4.1-kb transcripts in several tissue types. The smaller transcript was detected in the colon, whereas both forms were found in skeletal muscle.
Rozet et al. (1998) determined that the GLCLR gene encompasses 22 kb and contains 7 exons.
By fluorescence in situ hybridization (FISH), Tsuchiya et al. (1995) mapped the human GLCLR gene to 1p22-p21 and the mouse gene to 3H1-3. By Southern blot analysis of DNA from a panel of somatic cell hybrids, Sierra-Rivera et al. (1996) assigned GLCLR to chromosome 1; sublocalization to 1p21 was achieved by FISH.
Rozet et al. (1998) found an EST of GLCLR within a YAC contig encompassing the critically deleted region of human malignant mesothelioma, between loci D1S435 and D1S236. They refined the physical mapping of GLCLR to 1p22.1.
Nakamura et al. (2002) reported an association between a polymorphism in the GCLM gene (601176.0001) and myocardial infarction (608446).
Schizophrenia (181500) is a major and frequent chronic psychiatric disorder with a strong genetic component. Converging evidence points to the involvement of oxidative stress and N-methyl D-aspartate (NMDA) receptor (138249) hypofunction in the pathophysiology of the disease. As a main cellular nonprotein antioxidant and redox regulator, glutathione (GSH) plays a major role in protecting nervous tissue against reactive oxygen species and in modulating redox-sensitive sites, including NMDA receptors (NMDA-R). Tosic et al. (2006) noted that studies had found GSH levels to be decreased in patients' cerebrospinal fluid, in medial prefrontal cortex in vivo, and in striatum postmortem tissue. GSH-deficient models revealed morphologic, electrophysiologic, and behavioral anomalies similar to those observed in patients. Tosic et al. (2006) found an association between schizophrenia and the gene of the key GSH-synthesizing enzyme, GCLM. A functional role of the GCLM gene variance in schizophrenia was supported by its low expression in patients' fibroblasts and by the decreased stimulation of the enzyme activity when challenged by an oxidative stress. The findings were considered consistent with the concept that an abnormal GSH metabolism is a factor for schizophrenia. One of the case-control studies was conducted in Switzerland and the other in Denmark. Two particular combinations of variation at 3 SNPs related to the GCLM gene, TT/GG/TC and CC/GG/TT, had odds ratios of 4.89 and 4.17, respectively. Tosic et al. (2006) observed that the GCLM gene is localized on 1p21, a region shown by previous linkage studies to be one of the several critical for schizophrenia (Pulver et al., 2000, Arinami et al., 2005).
In Japanese patients with myocardial infarction (608446), Nakamura et al. (2002) searched for common variants in the 5-prime flanking region of the GCLM gene and identified a -588C-T polymorphism in which the T allele showed lower promoter activity (40 to 50% of that of the C allele) in response to oxidants. Analyzing 429 patients with MI and 428 controls, the authors found that the frequency of the T polymorphism was significantly higher in the MI group than in the control group (p less than 0.001). In multiple logistic regression analysis, the T polymorphism was a risk factor for MI independent of traditional coronary artery disease risk factors (OR = 1.98, 95% CI = 1.38-2.83, p less than 0.001). Nakamura et al. (2002) suggested that the -588T polymorphism may suppress oxidant induction of the GCLM gene and that it is a risk factor for MI.
Nakamura et al. (2003) examined the effects of the -588C-T polymorphism on coronary arterial diameter and blood flow responses to intracoronary infusion of acetylcholine in 157 consecutive patients with normal coronary angiograms. In multivariate linear regression analysis with covariates including traditional risk factors, the minor -588T allele had an independent association with impaired dilation of epicardial coronary arteries in response to acetylcholine (p less than 0.001), and it was independently associated with a blunted increase in coronary flow response to acetylcholine (p less than 0.01). In a subgroup of 59 consecutive patients, constrictor responses to intracoronary infusion of NG-monomethyl-L-arginine monoacetate, had an inverse and independent association with the -558T allele in multivariate analysis (p less than 0.01). Nakamura et al. (2003) concluded that the -588T polymorphism causes a decrease in endothelial nitric oxide bioactivity, leading to impairment of endothelium-dependent vasomotor function in large and resistance coronary arteries.
Arinami, T., Ohtsuki, T., Ishiguro, H., Ujike, H., Tanaka, Y., Morita, Y., Mineta, M., Takeichi, M., Yamada, S., Imamura, A., Ohara, K., Shibuya, H., and 40 others. Genomewide high-density SNP linkage analysis of 236 Japanese families supports the existence of schizophrenia susceptibility loci on chromosomes 1p, 14q, and 20p. Am. J. Hum. Genet. 77: 937-944, 2005. [PubMed: 16380906] [Full Text: https://doi.org/10.1086/498122]
Gipp, J. J., Bailey, H. H., Mulcahy, R. T. Cloning and sequencing of the cDNA for the light subunit of human liver gamma-glutamylcysteine synthetase and relative mRNA levels for heavy and light subunits in human normal tissues. Biochem. Biophys. Res. Commun. 206: 584-589, 1995. [PubMed: 7826375] [Full Text: https://doi.org/10.1006/bbrc.1995.1083]
Huang, C.-S., Anderson, M. E., Meister, A. Amino acid sequence and function of the light subunit of rat kidney gamma-glutamylcysteine synthetase. J. Biol. Chem. 268: 20578-20583, 1993. [PubMed: 8104188]
Nakamura, S., Kugiyama, K., Sugiyama, S., Miyamoto, S., Koide, S., Fukushima, H., Honda, O., Yoshimura, M., Ogawa, H. Polymorphism in the 5-prime-flanking region of human glutamate-cysteine ligase modifier subunit gene is associated with myocardial infarction. Circulation 105: 2968-2973, 2002. [PubMed: 12081989] [Full Text: https://doi.org/10.1161/01.cir.0000019739.66514.1e]
Nakamura, S., Sugiyama, S., Fujioka, D., Kawabata, K., Ogawa, H., Kugiyama, K. Polymorphism in glutamate-cysteine ligase modifier subunit gene is associated with impairment of nitric oxide-mediated coronary vasomotor function. Circulation 108: 1425-1427, 2003. [PubMed: 12975258] [Full Text: https://doi.org/10.1161/01.CIR.0000091255.63645.98]
Pulver, A. E., Mulle, J., Nestadt, G., Swartz, K. L., Blouin, J.-L., Dombroski, B., Liang, K.-Y., Housman, D. E., Kazazian, H. H., Antonarakis, S. E., Lasseter, V. K., Wolyniec, P. S., Thornquist, M. H., McGrath, J. A. Genetic heterogeneity in schizophrenia: stratification of genome scan data using co-segregating related phenotypes. Molec. Psychiat. 5: 650-653, 2000. [PubMed: 11126395] [Full Text: https://doi.org/10.1038/sj.mp.4000814]
Rozet, J.-M., Gerber, S., Perrault, I., Calvas, P., Souied, E., Chatelin, S., Viegas-Pequignot, E., Molina-Gomez, D., Munnich, A., Kaplan, J. Structure and refinement of the physical mapping of the gamma-glutamylcysteine ligase regulatory subunit (GLCLR) gene to chromosome 1pp22.1 within the critically deleted region of human malignant mesothelioma. Cytogenet. Cell Genet. 82: 91-94, 1998. [PubMed: 9841137] [Full Text: https://doi.org/10.1159/000015072]
Sierra-Rivera, E., Dasouki, M., Summar, M. L., Krishnamani, M. R. S., Meredith, M., Rao, P. N., Phillips, J. A., III, Freeman, M. L. Assignment of the human gene (GLCLR) that encodes the regulatory subunit of gamma-glutamylcysteine synthetase to chromosome 1p21. Cytogenet. Cell Genet. 72: 252-254, 1996. [PubMed: 8978789] [Full Text: https://doi.org/10.1159/000134202]
Tosic, M., Ott, J., Barral, S., Bovet, P., Deppen, P., Gheorghita, F., Matthey, M.-L., Parnas, J., Preisig, M., Saraga, M., Solida, A., Timm, S., Wang, A. G., Werge, T., Cuenod, M., Do, K. Q. Schizophrenia and oxidative stress: glutamate cysteine ligase modifier as a susceptibility gene. Am. J. Hum. Genet. 79: 586-592, 2006. [PubMed: 16909399] [Full Text: https://doi.org/10.1086/507566]
Tsuchiya, K., Mulcahy, R. T., Reid, L. L., Disteche, C. M., Kavanagh, T. J. Mapping of the glutamate-cysteine ligase catalytic subunit gene (GLCLC) to human chromosome 6p12 and mouse chromosome 9D-E and of the regulatory subunit gene (GLCLR) to human chromosome 1p21-p22 and mouse chromosome 3H1-3. Genomics 30: 630-632, 1995. [PubMed: 8825659] [Full Text: https://doi.org/10.1006/geno.1995.1293]