HGNC Approved Gene Symbol: EPHX2
Cytogenetic location: 8p21.2-p21.1 Genomic coordinates (GRCh38): 8:27,491,143-27,548,626 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8p21.2-p21.1 | {Hypercholesterolemia, familial, due to LDLR defect, modifier of} | 143890 | Autosomal dominant; Autosomal recessive | 3 |
Beetham et al. (1993) cloned a cDNA corresponding to soluble epoxide hydrolase from human liver. Sandberg and Meijer (1996) isolated a EPHX2 clone from a human genomic DNA library prepared from placental DNA. The coding sequence corresponded to 555 amino acids, which the authors noted included 1 additional residue compared to the reported cDNA sequence. Putative sites for phosphorylation, myristoylation, amidation, and peroxisomal targeting, as well as a leucine zipper, were detected.
In cardiac biopsies from subjects with ischemic heart failure and from controls, Monti et al. (2008) showed that expression of EPHX2 was decreased by 61.5% (p = 0.025) in subjects with heart failure compared with controls. They concluded that this finding supported transcriptional downregulation of EPHX2 as a potentially beneficial adaptive mechanism in human heart failure.
Hu et al. (2017) identified soluble epoxide hydrolase (EPHX2) as a key enzyme that initiates pericyte loss and breakdown of endothelial barrier function by generating the diol 19,20-dihydroxydocosapentaenoic acid, derived from docosahexaenoic acid. The expression of EPHX2 and the accumulation of 19,20-dihydroxydocosapentaenoic acid were increased in diabetic mouse retinas and in the retinas and vitreous humor of patients with diabetes. Mechanistically, the diol targeted the cell membrane to alter the localization of cholesterol-binding proteins, and prevented the association of presenilin-1 (104311) with N-cadherin (CDH2; 114020) and VE-cadherin (CDH5; 601120), thereby compromising pericyte-endothelial cell interactions and interendothelial cell junctions. Treating diabetic mice with a specific EPHX2 inhibitor prevented the pericyte loss and vascular permeability that are characteristic of nonproliferative diabetic retinopathy. Conversely, overexpression of EPHX2 in the retinal Muller glial cells of nondiabetic mice resulted in similar vessel abnormalities to those seen in diabetic mice with retinopathy. Hu et al. (2017) concluded that increased expression of EPHX2 is a key determinant in the pathogenesis of diabetic retinopathy, and that inhibition of this enzyme can prevent progression of the disease.
Sandberg and Meijer (1996) determined that the EPHX2 gene consists of 19 exons and is approximately 45 kb.
By fluorescence in situ hybridization, Larsson et al. (1995) mapped the EPHX2 gene to human 8p21-p12.
Grant et al. (1994) determined the chromosomal location of the murine soluble epoxide hydrolase gene by use of in situ hybridization, which localized it to band D of chromosome 14, and RFLP analysis of an intersubspecific testcross, which also assigned it to mouse chromosome 14. Simple sequence length polymorphism markers were then used to confirm the localization of the gene to a site 14 cM distal to the nucleoside phosphorylase gene and 19.2 cM proximal to D14Mit7. They used the symbol Ephs for the gene.
Cytosolic epoxide hydrolase is distinguished from the microsomal form (132810) by substrate specificity, molecular weight, and immunologic reactivity. Norris et al. (1989) found from twin studies that there was markedly less variability within monozygotic twins than within dizygotic, like-sex twins. In 100 unrelated male subjects, the extent of interindividual variation was 11-fold. Unimodal distribution of values among 99 subjects encompassed a 6-fold range. A study of 3 generations of the family of an outlier with very high activity demonstrated autosomal dominant inheritance. Analysis of 5 other families and of 12 sets of twins, all from the large unimodal distribution, yielded results consistent with either monogenic or polygenic control of variation. Also see Vesell (1991).
Sato et al. (2004) demonstrated a significant modification of the phenotype of familial hypercholesterolemia (see 143890) resulting from a defective allele at the LDLR locus (606945.0063) by the arg287 variation in the EPHX2 gene (132811.0001).
Fornage et al. (2005) genotyped 12 SNPs in the EPHX2 gene in 315 stroke patients and 1,021 controls from the ARIC study and identified 2 common EPHX2 haplotypes that were associated with increased and decreased risk of ischemic stroke (601367) in African Americans (adjusted p less than 0.04). In whites, 2 different common haplotypes showed suggestive evidence for association with ischemic stroke risk but, as in African Americans, these relationships were in opposite direction. Fornage et al. (2005) suggested that multiple variants may exist within or near the EPHX2 gene, with greatly contrasting relationships to ischemic stroke incidence.
Monti et al. (2008) performed invasive cardiac hemodynamic measurements in F2 crosses between spontaneously hypertensive heart failure (SHHF) rats and reference strains. The authors combined linkage analyses with genomewide expression profiling and identified Ephx2 as a heart failure susceptibility gene in SHHF rats. Specifically, Monti et al. (2008) found that cis variation at Ephx2 segregated with heart failure and with increased transcript expression, protein expression, and enzyme activity, leading to a more rapid hydrolysis of cardioprotective epoxyeicosatrienoic acids. To confirm their results, Monti et al. (2008) tested the role of Ephx2 in heart failure using knockout mice. Ephx2 gene ablation protected from pressure overload-induced heart failure and cardiac arrhythmias.
In a study of EPHX2 polymorphisms in 25 human liver specimens, Sandberg et al. (2000) observed an 860G-A substitution in exon 8 of the EPHX2 gene resulting in an arg287-to-gln (R287Q) substitution in 4 of 50 (8%) alleles. In an analysis of genomic DNA from 72 healthy individuals representing black, Asian, and white populations, Przybyla-Zawislak et al. (2003) identified the gln287 variant in 7% of alleles. In patient and control populations from Utah, however, Sato et al. (2004) found the gln287 allele to be more common, reporting a frequency of 84% among 160 control alleles and a frequency of 92% in 320 alleles from 160 members of a large Utah pedigree ascertained for familial hypercholesterolemia (see later).
Sato et al. (2004) described studies of the EPHX2 R287Q variant on the plasma total cholesterol and triglyceride phenotype in a very large Utah family with coronary artery disease studied by Takada et al. (2002). In studying 160 members of an 8-generation extended family with familial hypercholesterolemia (see 143890), they found that 69 members had type IIa hyperlipoproteinemia (i.e., high plasma cholesterol) and 10 had type IIb hyperlipoproteinemia (i.e., high plasma triglyceride as well as high plasma cholesterol). Intrafamilial correlation analysis of the modifier effect of the R287Q substitution in the EPHX2 gene was carried out among 79 mutation carriers of the LDLR mutation IVS14+1G-A (606945.0063) and 81 noncarriers. Half of the patients who presented with type IIb hyperlipoproteinemia had inherited a defective LDLR allele as well as an EPHX2-arg287 allele, whereas most who presented with type IIa hyperlipoproteinemia had a defective LDLR allele but not an EPHX2-arg287 allele. These results indicated a significant modification of the phenotype of familial hypercholesterolemia with defective LDLR allele by the arg287 variation. (The arg287-to-gln polymorphism was erroneously published as GLU287ARG in Sato et al., 2004).
In a study of coronary artery calcification in 1,201 African American individuals and 1,506 white individuals, Fornage et al. (2004) found that African American individuals with at least 1 copy of the gln287 allele had an approximately 2-fold greater risk of having coronary artery calcification, and the quantity of calcification was significantly greater, compared to those not carrying the allele. There was no relationship between the R287Q polymorphism and the probability of having coronary artery calcification in white participants.
Ohtoshi et al. (2005) evaluated insulin resistance and arg287gln status in 86 Japanese patients with type II diabetes (125853) and 205 controls and found that insulin resistance was significantly increased in type II diabetic patients with the 287gln allele. There was no association between the arg287gln polymorphism and insulin sensitivity in nondiabetic individuals.
Beetham, J. K., Tian, T., Hammock, B. D. cDNA cloning and expression of a soluble epoxide hydrolase from human liver. Arch. Biochem. Biophys. 305: 197-201, 1993. [PubMed: 8342951] [Full Text: https://doi.org/10.1006/abbi.1993.1411]
Fornage, M., Boerwinkle, E., Doris, P. A., Jacobs, D., Liu, K., Wong, N. D. Polymorphism of the soluble epoxide hydrolase is associated with coronary artery calcification in African-American subjects: the Coronary Artery Risk Development in Young Adults (CARDIA) study. Circulation 109: 335-339, 2004. [PubMed: 14732757] [Full Text: https://doi.org/10.1161/01.CIR.0000109487.46725.02]
Fornage, M., Lee, C. R., Doris, P. A., Bray, M. S., Heiss, G., Zeldin, D. C., Boerwinkle, E. The soluble epoxide hydrolase gene harbors sequence variation associated with susceptibility to and protection from incident ischemic stroke. Hum. Molec. Genet. 14: 2829-2837, 2005. [PubMed: 16115816] [Full Text: https://doi.org/10.1093/hmg/ddi315]
Grant, D. F., Spearow, J. L., Storms, D. H., Edelhoff, S., Adler, D. A., Disteche, C. M., Taylor, B. A., Hammock, B. D. Chromosomal mapping and expression levels of a mouse soluble epoxide hydrolase gene. Pharmacogenetics 4: 64-72, 1994. [PubMed: 7915936] [Full Text: https://doi.org/10.1097/00008571-199404000-00003]
Hu, J., Dziumbla, S., Lin, J., Bibli, S.-I., Zukunft, S., de Mos, J., Awwad, K., Fromel, T., Jungmann, A., Devraj, K., Cheng, Z., Wang, L., and 10 others. Inhibition of soluble epoxide hydrolase prevents diabetic retinopathy. Nature 552: 248-252, 2017. [PubMed: 29211719] [Full Text: https://doi.org/10.1038/nature25013]
Larsson, C., White, I., Johansson, C., Stark, A., Meijer, J. Localization of the human soluble epoxide hydrolase gene (EPHX2) to chromosomal region 8p21-p12. Hum. Genet. 95: 356-358, 1995. [PubMed: 7868134] [Full Text: https://doi.org/10.1007/BF00225209]
Monti, J., Fischer, J., Paskas, S., Heinig, M., Schulz, H., Gosele, C., Heuser, A., Fischer, R., Schmidt, C., Schirdewan, A., Gross, V., Hummel, O., and 13 others. Soluble epoxide hydrolase is a susceptibility factor for heart failure in a rat model of human disease. Nature Genet. 40: 529-537, 2008. [PubMed: 18443590] [Full Text: https://doi.org/10.1038/ng.129]
Norris, K. K., DeAngelo, T. M., Vesell, E. S. Genetic and environmental factors that regulate cytosolic epoxide hydrolase activity in normal human lymphocytes. J. Clin. Invest. 84: 1749-1756, 1989. [PubMed: 2592558] [Full Text: https://doi.org/10.1172/JCI114358]
Ohtoshi, K., Kaneto, H., Node, K., Nakamura, Y., Shiraiwa, T., Matsuhisa, M., Yamasaki, Y. Association of soluble epoxide hydrolase gene polymorphism with insulin resistance in type 2 diabetic patients. Biochem. Biophys. Res. Commun. 331: 347-350, 2005. [PubMed: 15845398] [Full Text: https://doi.org/10.1016/j.bbrc.2005.03.171]
Przybyla-Zawislak, B. D., Srivastava, P. K., Vazquez-Matias, J., Mohrenweiser, H. W., Maxwell, J. E., Hammock, B. D., Bradbury, J. A., Enayetallah, A. E., Zeldin, D. C., Grant, D. F. Polymorphisms in human soluble epoxide hydrolase. Molec. Pharm. 64: 482-490, 2003. [PubMed: 12869654] [Full Text: https://doi.org/10.1124/mol.64.2.482]
Sandberg, M., Hassett, C., Adman, E. T., Meijer, J., Omiecinski, C. J. Identification and functional characterization of human soluble epoxide hydrolase genetic polymorphisms. J. Biol. Chem. 275: 28873-28881, 2000. [PubMed: 10862610] [Full Text: https://doi.org/10.1074/jbc.M001153200]
Sandberg, M., Meijer, J. Structural characterization of the human soluble epoxide hydrolase gene (EPHX2). Biochem. Biophys. Res. Commun. 221: 333-339, 1996. [PubMed: 8619856] [Full Text: https://doi.org/10.1006/bbrc.1996.0596]
Sato, K., Emi, M., Ezura, Y., Fujita, Y., Takada, D., Ishigami, T., Umemura, S., Xin, Y., Wu, L. L., Larrinaga-Shum, S., Stephenson, S. H., Hunt, S. C., Hopkins, P. N. Soluble epoxide hydrolase variant (glu287arg) modifies plasma total cholesterol and triglyceride phenotype in familial hypercholesterolemia: intrafamilial association study in an eight-generation hyperlipidemic kindred. J. Hum. Genet. 49: 29-34, 2004. [PubMed: 14673705] [Full Text: https://doi.org/10.1007/s10038-003-0103-6]
Takada, D., Emi, M., Ezura, Y., Nobe, Y., Kawamura, K., Iino, Y., Katayama, Y., Xin, Y., Wu, L. L., Larringa-Shum, S., Stephenson, S. H., Hunt, S. C., Hopkins, P. N. Interaction between the LDL-receptor gene bearing a novel mutation and a variant in the apolipoprotein A-II promoter: molecular study in a 1135-member familial hypercholesterolemia kindred. J. Hum. Genet. 47: 656-664, 2002. [PubMed: 12522687] [Full Text: https://doi.org/10.1007/s100380200101]
Vesell, E. S. Genetic factors that regulate cytosolic epoxide hydrolase activity in normal human lymphocytes. Ann. Genet. 34: 167-172, 1991. [PubMed: 1809223]