HGNC Approved Gene Symbol: EPX
SNOMEDCT: 711160007;
Cytogenetic location: 17q22 Genomic coordinates (GRCh38): 17:58,192,726-58,205,174 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q22 | [Eosinophil peroxidase deficiency] | 261500 | Autosomal recessive | 3 |
Human eosinophil peroxidase (EC 1.11.1.7) is a heme-containing glycoprotein that is present in lysosomes of eosinophilic granulocytes. EPX has been purified from human eosinophils and from eosinophilic leukemia cells. The purified enzyme has been shown to have a molecular mass of about 70 kD and to be composed of 1 heavy chain and 1 light chain. In contrast to myeloperoxidase (MPO; 606989), eosinophil peroxidase uses bromide instead of chloride to generate a halogenating oxidant. Myeloperoxidase is more sensitive to cyanide than eosinophil peroxidase; antibodies directed against human eosinophil peroxidase do not neutralize myeloperoxidase and vice versa (summary by Sakamaki et al., 1989).
Sakamaki et al. (1989) used human myeloperoxidase cDNA as a probe to isolate a gene which, from its sequence, was concluded to encode human eosinophil peroxidase. EPX encodes a deduced 715-amino acid protein. The heavy chain and the light chain of eosinophil peroxidase were located on the COOH and NH2 terminus of the protein, respectively, both chains being coded by a single mRNA, as is the case with myeloperoxidase. The coding sequences of eosinophil peroxidase and myeloperoxidase showed homologies of 72.4% at the nucleotide and 69.8% at the amino acid level, while little homology was found in the 5-prime flanking region.
The EPX gene contains 12 exons and spans about 12 kb (Sakamaki et al., 1989).
By somatic cell hybrid analysis and in situ hybridization, Sakamaki et al. (2000) mapped the EPX gene to 17q23.1 in a cluster with lactoperoxidase (LPO; 150205) and myeloperoxidase.
Romano et al. (1994) reported the molecular characterization of eosinophil peroxidase in a man with deficiency of this enzyme (EPXD; 261500) and his family members. His eosinophils contained EPX-related material as determined immunochemically using either monoclonal or polyclonal anti-EPX antibodies but had no spectroscopic evidence of the enzyme. Eosinophil precursors from the proband contained normal-sized EPX mRNA, which was reverse transcribed into the corresponding cDNA encompassing the whole gene. Sequence of the cDNA disclosed 2 mutations, a G-to-A transition causing a nonconservative replacement of an arginine residue with a histidine (R286H; 131399.0001) and an insertion causing a shift in the reading frame with appearance of a premature stop codon (131399.0002). Both the son and the daughter of the proband inherited the G-to-A transition and their eosinophils contained a peroxidase activity intermediate between that of control subjects and the proband, suggesting that the transition is a deficiency-causing mutation. Eosinophil precursors from the proband were found to synthesize actively a peroxidase that was apparently normal in terms of cytochemical reaction and immunoreactivity, but spectroscopically abnormal. The cytochemical reaction for peroxidase tended to decrease or disappear in the eosinophil precursors of the proband but not in those of a normal subject, suggesting that the R286H substitution results in the synthesis of an unstable EPX that undergoes progressive degradation as the cells mature.
In a man with eosinophil peroxidase deficiency, Nakagawa et al. (2001) identified homozygosity for a mutation in the EPX gene (131399.0003). His wife was homozygous wildtype, and his son and daughter were heterozygous for the mutation. Cytochemical analysis of the proband's children showed a completely normal display.
In a blood donor at the blood bank of Trieste Hospital, Romano et al. (1994) identified a man with eosinophil peroxidase deficiency (EPXD; 261500) who was found to be compound heterozygous for 2 mutations in the EPX gene. One was a G-to-A transition at position 857 that predicted the nonconservative substitution of histidine for arginine at codon 286 (R286H). Both his son and his daughter had inherited this mutation in heterozygous state. The other chromosome carried an insertion of a G within the G tract 1537-1541 at the intron-exon 10 junction (131399.0002). This caused a shift in the reading frame with the generation of a stop codon after codon 538, leading to a truncated EPX precursor that lacked 177 amino acids and had a completely subverted sequence of the 24-amino acid carboxyl-terminal tail downstream of the insertion. To establish that the 2 mutations were located on different chromosomes, a cDNA fragment corresponding to a region including both mutations (nucleotides 659-1608) was amplified by PCR, cloned, and sequenced. Each clone was found to contain only 1 of the 2 mutations, indicating the compound heterozygosity.
For discussion of the 1-bp insertion in the EPX gene (1537insG) that was found in compound heterozygous state in a patient with eosinophil peroxidase deficiency (EXPD; 261500) by Romano et al. (1994), see 131399.0001.
In a 62-year-old man who was found to have eosinophil peroxidase deficiency (EPXD; 261500) during routine blood testing, Nakagawa et al. (2001) identified a homozygous g.2060G-A transition in exon 11 of the EPX gene, resulting in an asp648-to-asn (D648N) substitution. His wife carried 2 wildtype alleles, whereas his son and daughter were heterozygous for the mutation. Cytochemical blood analysis in the proband's children showed a completely normal display. Using a structural model of EPX based on myeloperoxidase, Nakagawa et al. (2001) located asp648 on the inside of the molecule fixed to arg146 by electrostatic interaction and hydrogen bonds. They proposed that a change from asp to asn would cause loss of the electrostatic interaction with arg146, which is crucial for disulfide bonds of the light chain in the N terminus.
Nakagawa, T., Ikemoto, T., Takeuchi, T., Tanaka, K., Tanigawa, N., Yamamoto, D., Shimizu, A. Eosinophilic peroxidase deficiency: identification of a point mutation (D648N) and prediction of structural changes. (Abstract) Hum. Mutat. 17: 235-236, 2001. Note: Full article online. [PubMed: 11241847] [Full Text: https://doi.org/10.1002/humu.10]
Romano, M., Patriarca, P., Melo, C., Baralle, F. E., Dri, P. Hereditary eosinophil peroxidase deficiency: immunochemical and spectroscopic studies and evidence for a compound heterozygosity of the defect. Proc. Nat. Acad. Sci. 91: 12496-12500, 1994. [PubMed: 7809065] [Full Text: https://doi.org/10.1073/pnas.91.26.12496]
Sakamaki, K., Kanda, N., Ueda, T., Aikawa, E., Nagata, S. The eosinophil peroxidase gene forms a cluster with the genes for myeloperoxidase and lactoperoxidase on human chromosome 17. Cytogenet. Cell Genet. 88: 246-248, 2000. [PubMed: 10828600] [Full Text: https://doi.org/10.1159/000015529]
Sakamaki, K., Tomonaga, M., Tsukui, K., Nagata, S. Molecular cloning and characterization of a chromosomal gene for human eosinophil peroxidase. J. Biol. Chem. 264: 16828-16836, 1989. [PubMed: 2550461]