HGNC Approved Gene Symbol: GLO1
Cytogenetic location: 6p21.2 Genomic coordinates (GRCh38): 6:38,675,925-38,703,145 (from NCBI)
Glyoxalase I (EC 4.4.1.5) is a glutathione-binding protein involved in the detoxification of methylglyoxal, a byproduct of glycolysis. GLO1 and glyoxalase II (GLO2; 138760) catalyze successive steps in the pathway. GLO1 catalyzes condensation of methylglyoxal and reduced glutathione to form S-lactoyl-glutathione; GLO2 (hydroxyacyl glutathione hydrolase) converts the latter substance to D-lactic acid and reduced glutathione (Ranganathan et al., 1999).
Kim et al. (1993) isolated a cDNA corresponding to the GLO1 gene from a human monocyte cDNA library. The cDNA predicts a 184-amino acid protein with M(r) 20,719.
Ranganathan et al. (1993) isolated a GLO1 cDNA from a human colon cDNA library. The human enzyme showed 42% amino acid homology with bacterial Glo1. Northern blot analysis identified a 2.2-kb mRNA transcript in colon tissue. There was a 12-fold increase of the GLO1 transcript in colon carcinoma tissue compared to normal colon tissue from the same patient, and the authors concluded that GLO1 gene expression was induced in colon carcinoma. Ranganathan et al. (1999) identified an insulin response element (IRE) and zinc metal response element (MRE) in the promoter region of the GLO1 gene.
Ranganathan et al. (1999) determined that the GLO1 gene contains 5 exons. Using bioinformatics, Gale and Grant (2004) found that the GLO1 gene contains 6 exons with evidence of possible alternative splicing.
Reinsmoen et al. (1977) presented evidence from the family data that GLO is linked to HLA and that the order of loci on chromosome 6p is HLA-A, HLA-B, HLA-D, GLO, centromere. Meo et al. (1977) found that in the mouse glyoxalase I maps approximately 3 cM from the Ss locus, a component of the major histocompatibility complex, H-2. GLO1 has no known functional relationship to MHC.
From study of a 3-generation family segregating for variation of the centromeric heterochromatic region of chromosome 6p11, Bakker et al. (1979) concluded that the HLA cluster and 6ph are about 6 cM apart (with peak lod score of 3.466), that GLO is on the centromeric side of HLA, that PGM3 (172100) is not on the short arm, and that HLA-B is closer to the centromere than HLA-A.
Hansen and Eriksen (1979) found a maximum lod score of 14.6 at theta = 0.060 for linkage of HLA and GLO1. Goldman et al. (1991) confirmed the linkage by study of 2-dimensional electrophoresis in CEPH families. Blanche et al. (1991) presented a genetic map of 6p which involved RFLP mapping of the GLO1 locus.
Kompf et al. (1975) found that red cell GLO1 is polymorphic in man.
Junaid et al. (2004) presented evidence suggesting that an ala111-to-glu polymorphism in the GLO1 gene (A111E; 138750.0001) may be a susceptibility factor for the development of autism (see 209850). This suggestion was not confirmed in studies by Rehnstrom et al. (2008) and Wu et al. (2008) in Finnish and Han Chinese populations, respectively.
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
Chen et al. (2004) found that the Glo1 gene was upregulated approximately 1.6-fold in brain tissue of a transgenic mouse model of Alzheimer disease (AD; 104300) and frontotemporal dementia (600274). The transgenic mice carried the pro301-to-leu mutation in the tau gene (P301L; 157140.0001) and developed neurofibrillary tangles. GLO1 was also elevated in human Alzheimer disease brains compared to nondemented controls, and GLO1 immunohistochemistry detected intensely stained flame-shaped neurons in AD brains. The data demonstrated the potential of transcriptomics applied to animal models of human diseases and suggested a previously unidentified role for glyoxalase I in neurodegenerative disease.
Using a combination of behavioral analysis of 6 inbred mouse strains with quantitative gene expression profiling of several brain regions, Hovatta et al. (2005) identified 17 genes with expression patterns that correlated with anxiety-like behavioral phenotypes. To determine if 2 of the genes, glyoxalase-1 and glutathione reductase-1 (138300), have a causal role in the genesis of anxiety, Hovatta et al. (2005) performed genetic manipulation using lentivirus-mediated gene transfer. Local overexpression of these genes in the mouse brain resulted in increased anxiety-like behavior, while local inhibition of glyoxalase-1 expression by RNA interference decreased the anxiety-like behavior. Hovatta et al. (2005) concluded that both of these genes are involved in oxidative stress metabolism, linking this pathway with anxiety-related behavior.
This variant, formerly titled AUTISM, SUSCEPTIBILITY TO, has been reclassified based on the findings of Rehnstrom et al. (2008) and Wu et al. (2008).
Using a proteomics method to identify abnormal proteins in autopsied brains of patients with autism (209850), Junaid et al. (2004) found an increase in polarity of glyoxalase I by 2-dimensional gel electrophoresis; direct sequencing of the GLO1 gene identified a 419C-A transversion in the gene, resulting in an ala111-to-glu (A111E) substitution. The glu111 enzyme is more acidic than the ala111 enzyme and has reduced functional activity. Four brains were homozygous for A/A (glu111), 3 were heterozygous for A/C (ala111/glu111), and 1 was homozygous for C/C (ala111). Of 9 controls, which included 1 patient with Down syndrome and 3 patients with mental retardation, 2 were A/A, 3 were A/C, and 4 were C/C. In a larger sample of autism patients and controls, the frequency of the 419A allele was 0.6 in autism and 0.4 in controls. Junaid et al. (2004) suggested that a reduction in GLO1 enzyme activity could result in the accumulation of methylglyoxal, which may be toxic to the developing brain. The data suggested that homozygosity for the glu111 allele is a predisposing factor in the development of autism.
Rehnstrom et al. (2008) genotyped 6 polymorphisms in the GLO1 gene, including A111E, in Finnish families with more than 230 individuals with autism spectrum disorders and carried out both linkage and association analyses. They observed no significant linkage or association between any SNP and ASD.
Wu et al. (2008) performed mutation screening of all exons of the GLO1 gene in 272 Han Chinese patients with autism and 310 healthy controls. They found no significant differences in the frequency distributions of A111E between the autism and control groups. Moreover, they did not identify any other mutations associated with autism in the exon regions.
Bakker, E., Pearson, P. L., Meera Khan, P., Schreuder, G. M. T., Madan, K. Orientation of major histocompatibility (MHC) genes relative to the centromere of human chromosome 6. Clin. Genet. 15: 198-202, 1979. [PubMed: 761421] [Full Text: https://doi.org/10.1111/j.1399-0004.1979.tb01762.x]
Bender, K., Grzeschik, K. H. Assignment of the genes for human glyoxalase I to chromosome 6 and for human esterase D to chromosome 13. Cytogenet. Cell Genet. 16: 93-96, 1976. [PubMed: 975931] [Full Text: https://doi.org/10.1159/000130561]
Beretta, M., Schiliro, G., Russo, A., Barbujani, G., Mazzetti, P., Russo, G., Barrai, I. A new rare variant of the glyoxalase I system of the red cell: GLO-Sicily. Am. J. Hum. Genet. 35: 1042-1047, 1983. [PubMed: 6613997]
Blanche, H., Zoghbi, H. Y., Jabs, E. W., de Gouyon, B., Zunec, R., Dausset, J., Cann, H. M. A centromere-based genetic map of the short arm of human chromosome 6. Genomics 9: 420-428, 1991. [PubMed: 2032717] [Full Text: https://doi.org/10.1016/0888-7543(91)90407-6]
Carter, N. D., West, C. M., Bernard, J. M., Farid, N. R., Larsen, B., Marshall, W. H. Linkage of glyoxalase I and HLA in two Newfoundland communities. Hum. Hered. 28: 397-400, 1978. [PubMed: 680701] [Full Text: https://doi.org/10.1159/000152982]
Chen, F., Wollmer, M. A., Hoerndli, F., Munch, G., Kuhla, B., Rogaev, E. I., Tsolaki, M., Papassotiropoulos, A., Gotz, J. Role for glyoxalase I in Alzheimer's disease. Proc. Nat. Acad. Sci. 101: 7687-7692, 2004. [PubMed: 15128939] [Full Text: https://doi.org/10.1073/pnas.0402338101]
Gale, C. P., Grant, P. J. The characterisation and functional analysis of the human glyoxalase-1 gene using methods of bioinformatics. Gene 340: 251-260, 2004. [PubMed: 15475166] [Full Text: https://doi.org/10.1016/j.gene.2004.07.009]
Giblett, E. R., Lewis, M. Gene linkage studies on glyoxalase I. Cytogenet. Cell Genet. 16: 313 only, 1976. [PubMed: 975897] [Full Text: https://doi.org/10.1159/000130618]
Goldman, D., O'Brien, S. J., Lucas-Derse, S., Dean, M. Linkage mapping of human polymorphic proteins identified by two-dimensional electrophoresis. Genomics 11: 875-884, 1991. [PubMed: 1686020] [Full Text: https://doi.org/10.1016/0888-7543(91)90010-c]
Hansen, H. E., Eriksen, B. HLA-GLO linkage analysis in 57 informative families. Hum. Hered. 29: 355-360, 1979. [PubMed: 511191] [Full Text: https://doi.org/10.1159/000153072]
Hovatta, I., Tennant, R. S., Helton, R., Marr, R. A., Singer, O., Redwine, J. M., Ellison, J. A., Schadt, E. E., Verma, I. M., Lockhart, D. J., Barlow, C. Glyoxalase 1 and glutathione reductase 1 regulate anxiety in mice. Nature 438: 662-666, 2005. [PubMed: 16244648] [Full Text: https://doi.org/10.1038/nature04250]
Junaid, M. A., Kowal, D., Barua, M., Pullarkat, P. S., Sklower Brooks, S., Pullarkat, R. K. Proteomic studies identified a single nucleotide polymorphism in glyoxalase I as autism susceptibility factor. Am. J. Med. Genet. 131A: 11-17, 2004. [PubMed: 15386471] [Full Text: https://doi.org/10.1002/ajmg.a.30349]
Karlsson, S., Arnason, A., Jensson, O. GLO polymorphism in Iceland. Hum. Hered. 30: 383-385, 1980. [PubMed: 7216230] [Full Text: https://doi.org/10.1159/000153163]
Kavathas, P., DeMars, R. A new variant glyoxalase I allele that is readily detectable in stimulated lymphocytes and lymphoblastoid cell lines but not in circulating lymphocytes or erythrocytes. Am. J. Hum. Genet. 33: 935-945, 1981. [PubMed: 7325156]
Kim, N. S., Umezawa, Y., Ohmura, S., Kato, S. Human glyoxalase I: cDNA cloning, expression, and sequence similarity to glyoxalase I from Pseudomonas putida. J. Biol. Chem. 268: 11217-11221, 1993. [PubMed: 7684374]
Kompf, J., Bissbort, S., Gussmann, S., Ritter, H. Polymorphism of red cell glyoxalase I (E.C.4.4.1.5), a new genetic marker in man: investigation of 169 mother-child combinations. Humangenetik 27: 141-143, 1975. [PubMed: 1150236] [Full Text: https://doi.org/10.1007/BF00273329]
Kompf, J., Bissbort, S., Ritter, H. Red cell glyoxalase I (E.C.4.4.1.5): formal genetics and linkage relations. Humangenetik 28: 249-251, 1975. [PubMed: 1150284] [Full Text: https://doi.org/10.1007/BF00278552]
Kompf, J., Siebert, G., Ritter, H., Heilbronner, H., Schunter, F., Wernet, P., Gupta, D., Moeller, H. Data on linkage relations between GLO and 21-hydroxylase. Hum. Genet. 54: 419-420, 1980. [PubMed: 6967447] [Full Text: https://doi.org/10.1007/BF00291592]
Meo, T., Douglas, T., Rijnbeek, A.-M. Glyoxalase I polymorphism in the mouse: a new genetic marker linked to H-2. Science 198: 311-313, 1977. [PubMed: 910130] [Full Text: https://doi.org/10.1126/science.910130]
Olaisen, B., Gedde-Dahl, T., Jr., Thorsby, E. Localization of the human GLO gene locus. Hum. Genet. 32: 301-304, 1976. [PubMed: 939550] [Full Text: https://doi.org/10.1007/BF00295820]
Parr, C. W., Bagster, I. A., Welch, S. G. Human red cell glyoxalase I polymorphism. Biochem. Genet. 15: 109-114, 1977. [PubMed: 66916] [Full Text: https://doi.org/10.1007/BF00484553]
Ranganathan, S., Ciaccio, P. J., Walsh, E. S., Tew, K. D. Genomic sequence of human glyoxalase-I: analysis of promoter activity and its regulation. Gene 240: 149-155, 1999. [PubMed: 10564821] [Full Text: https://doi.org/10.1016/s0378-1119(99)00420-5]
Ranganathan, S., Walsh, E. S., Godwin, A. K., Tew, K. D. Cloning and characterization of human colon glyoxalase-I. J. Biol. Chem. 268: 5661-5667, 1993. [PubMed: 8449929]
Rehnstrom, K., Ylisaukko-oja, T., Vanhala, R., von Wendt, L., Peltonen, L., Hovatta, I. No association between common variants in glyoxalase 1 and autism spectrum disorders. Am. J. Med. Genet. 147B: 124-127, 2008. [PubMed: 17722011] [Full Text: https://doi.org/10.1002/ajmg.b.30582]
Reinsmoen, N. L., Friend, P. S., Miller, W. V., Burgdorf, A., Giblett, E. R., Yunis, E. J. Inheritance of recombinant HLA-GLO haplotype suggesting the gene sequence. Nature 267: 276-278, 1977. [PubMed: 141008] [Full Text: https://doi.org/10.1038/267276a0]
Roychoudhury, A. K., Nei, M. Human Polymorphic Genes: World Distribution. New York: Oxford Univ. Press (pub.) 1988.
Rubinstein, P., Suciu-Foca, N. Glyoxalase 1: a possible 'null' allele. Hum. Hered. 29: 217-220, 1979. [PubMed: 478555] [Full Text: https://doi.org/10.1159/000153047]
Schimandle, C. M., Vander Jagt, D. L. Isolation and kinetic analysis of the multiple forms of glyoxalase-1 from human erythrocytes. Arch. Biochem. Biophys. 195: 261-268, 1979. [PubMed: 475391] [Full Text: https://doi.org/10.1016/0003-9861(79)90352-7]
Sparkes, R. S., Sparkes, M. C., Crist, M., Anderson, C. E. Glyoxalase I 'null' allele in a new family: identification by abnormal segregation pattern and quantitative assay. Hum. Genet. 64: 146-147, 1983. [PubMed: 6885048] [Full Text: https://doi.org/10.1007/BF00327112]
Teng, Y. S., Tan, S. G., Lopez, C. G. Red cell glyoxalase I and placental soluble aconitase polymorphisms in the three major ethnic groups of Malaysia. Jpn. J. Hum. Genet. 23: 211-215, 1978. [PubMed: 732016] [Full Text: https://doi.org/10.1007/BF01872470]
Whittington, J. E., Keats, B. J. B., Jackson, J. F., Currier, R. D., Terasaki, P. I. Linkage studies on glyoxalase I (GLO), pepsinogen (PG), spinocerebellar ataxia (SCA1), and HLA. Cytogenet. Cell Genet. 28: 145-150, 1980. [PubMed: 7438789] [Full Text: https://doi.org/10.1159/000131524]
Wu, Y.-Y., Chien, W.-H., Huang, Y.-S., Gau, S. S.-F., Chen, C.-H. Lack of evidence to support the glyoxalase 1 gene (GLO1) as a risk gene of autism in Han Chinese patients from Taiwan. Prog. Neuropsychopharmacol. Biol. Psychiatry 32: 1740-1744, 2008. [PubMed: 18721844] [Full Text: https://doi.org/10.1016/j.pnpbp.2008.07.019]
Ziegler, A., Fonatsch, C., Kompf, J. Mapping of the locus for glyoxalase 1 (GLO1) on human chromosome 6 using mutant cell lines. (Abstract) Cytogenet. Cell Genet. 40: 787 only, 1985.