Alternative titles; symbols
HGNC Approved Gene Symbol: PXDN
Cytogenetic location: 2p25.3 Genomic coordinates (GRCh38) : 2:1,631,887-1,744,901 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p25.3 | Anterior segment dysgenesis 7, with sclerocornea | 269400 | Autosomal recessive | 3 |
Drosophila peroxidasin is an extracellular matrix-associated peroxidase. It is expressed exclusively in hemocytes derived from head mesoderm at a very early stage of differentiation. Peroxidasin exists as a homotrimer with a unique hybrid structure that combines an enzymatically functional peroxidase domain with motifs that are typically found in extracellular matrix-associated proteins. It is a secreted protein that contains a secretory recognition sequence at its N terminus. Peroxidasin catalyzes hydrogen peroxide-driven radioiodination, oxidations, and the formation of dityrosine in vitro. It is also thought to function in extracellular matrix consolidation, phagocytosis, and defense. PRG2 encodes a human homolog of Drosophila peroxidasin (summary by Horikoshi et al., 1999).
Weiler et al. (1994) determined that PRG2, which they called MG50, was expressed in a restricted pattern. Its 8.5-kb mRNA was found in melanoma cell lines and in a fibroblast, a glioblastoma, and a breast carcinoma line, but not in colon carcinoma lines, a myeloid leukemia line, or a Burkitt lymphoma cell line.
By sequencing random cDNAs corresponding to relatively long transcripts from the human immature myeloid cell line KG-1, Nagase et al. (1996) identified a cDNA, which they called KIAA0230, that encodes PRG2. The cDNA represents at least 90% of the full-length PRG2 transcript; however, since it lacks an in-frame stop codon upstream of the first ATG, it may be missing 5-prime coding sequence. The 1,496-amino acid PRG2 protein deduced from the cDNA sequence contains predicted transmembrane domains. PRG2 shares 38% amino acid sequence identity with Drosophila peroxidasin across 1,412 amino acids. Northern blot analysis of human tissues showed PRG2 expression at higher levels in heart, lung, ovary, and placenta, and lower levels in liver, small intestine, colon, pancreas, spleen, kidney, thymus, skeletal muscle, testis, and prostate; PRG2 expression was not detected in brain or peripheral blood leukocytes.
To identify genes that may be involved in p53 (TP53; 191170)-dependent apoptosis, Horikoshi et al. (1999) used differential display analysis to compare mRNA from a human colon cancer cell line undergoing a very early stage of p53-induced apoptosis to mRNA from the same cell line before undergoing apoptosis. They identified 6 p53-responsive genes, PRG1 (605157) to PRG6 (605162). PRG2 was upregulated in the apoptotic cells. Horikoshi et al. (1999) noted that the sequence of PRG2 is identical to that of KIAA0230, which encodes a protein similar to Drosophila peroxidasin (Nagase et al., 1996). Horikoshi et al. (1999) concluded that PRG2 is a human homolog of Drosophila peroxidasin. The predicted human PRG2 protein contains a signal sequence, leucine-rich repeats, 4 C2-type immunoglobulin domains, a peroxidase domain, and a cysteine-rich motif found in thrombospondins and procollagens. The amino acid sequence of the PRG2 peroxidase domain is very similar to the sequences of the peroxidase domains of myeloperoxidase (MPO; 606989), eosinophil peroxidase (EPX; 131399), lactoperoxidase (LPO; 150205), and thyroid peroxidase (TPO; 274500). Northern blot analysis detected a 7.5-kb PRG2 transcript in all normal human tissues examined except brain and leukocytes, and a 4.5-kb PRG2 transcript in testis and the p53-induced colon cancer cell line. The authors characterized the 4.5-kb transcript and found that it lacked the 5-prime portion of the 7.5-kb transcript but encoded a complete peroxidase domain.
Using DUOX1 (606758) to query an EST database, Cheng et al. (2008) identified PXDN, which they called VPO1, and PXDNL (615904), which they called VPO2. Both are large multidomain proteins that share 63% identity. They each have an N-terminal signal sequence, followed by a leucine-rich repeat (LRR) N-terminal domain, 5 LRRs, an LRR C-terminal domain, 4 immunoglobulin C2-type domains, a peroxidase domain, and a von Willebrand factor type C (VWFC; see 613160) domain at the extreme C terminus. Using RT-PCR, Cheng et al. (2008) detected variable Vpo1 expression in all adult mouse tissues examined and in mouse embryos at all developmental time points examined. Western blot analysis detected robust Vpo1 expression in mouse heart, with little to no expression in the other 7 tissues examined. Immunohistochemical analysis of mouse carotid artery detected Vpo1 in both endothelium and smooth muscle cells.
Khan et al. (2011) investigated the distribution of peroxidasin protein in mouse embryonic and adult eyes, and observed localization of Pxdn to the corneal epithelial layer at embryonic day (E) 18.5 and at postnatal day 60. There was also localization to the lens epithelium in adult eyes.
By immunohistochemical studies in mouse embryos, Yan et al. (2014) demonstrated faint expression of peroxidasin in the epithelial and primary fiber cells of the just-formed lens vesicle at E11.5. At E13.5, peroxidasin was strongly expressed in the developing lens, especially in the epithelium and inner limiting membrane, as well as in ocular mesenchymal cells in the vitreous. At E17.5, peroxidasin was expressed in the whole lens, particularly the epithelium and posterior pole, and in the inner neuroblast layer of the eye.
Cheng et al. (2008) determined that the PXDN gene contains 23 exons and spans approximately 110 kb.
By analysis of somatic cell hybrid and radiation hybrid mapping panels, Nagase et al. (1996) mapped the PRG2 gene to chromosome 2. By FISH, Weiler et al. (1994) mapped the PRG2 (MG50) gene to chromosome 2p25.3.
Cheng et al. (2008) found that mouse Vpo1 was a heme-dependent peroxidase that used either exogenously added H2O2 or H2O2 produced in cells by coexpressed NADPH oxidases (see 300225). Heme maintained its association with Vpo1 during SDS-PAGE, suggesting that heme was covalently bound to Vpo1.
In 2 unrelated Pakistani families with corneal opacification, congenital cataract, and microcornea mapping to chromosome 2p (ASMD7; 269400), and in a Cambodian family with severe corneal opacification and buphthalmos mapping to 2p, Khan et al. (2011) identified homozygosity for 3 different mutations in the PXDN gene: a 1-bp deletion (605158.0001), a missense mutation (R880C; 605158.0002), and a nonsense mutation (R341X; 605158.0003), respectively. The mutations, which segregated with disease in each of the families, were not found in ethnically matched controls.
In a brother and sister and an unrelated boy with anterior segment dysgenesis, Choi et al. (2015) identified compound heterozygosity for mutations in the PXDN gene (see, e.g., 605158.0003 and 605158.0004).
Yan et al. (2014) described a Pxdn mouse mutant induced by N-ethyl-N-nitrosourea (ENU), which resulted in a recessive small-eye phenotype. Sequence analysis revealed a 3816T-A transversion in exon 19 of Pxdn, resulting in a C1272X substitution in the peroxidase domain. The mice exhibited severe anterior segment dysgenesis and microphthalmia, as well as early-onset glaucoma and progressive retinal dysgenesis, resembling the manifestations in patients with PXDN mutations. The proliferation and differentiation of the lens is disrupted in association with aberrant expression of the transcription factor genes Pax6 (607108) and Foxe3 (601094) in mutant eyes. In addition, Pxdn is involved in basement membrane consolidation and lens epithelium adhesion in the ocular lens. Impaired anterior segment development causes local loss of structural integrity in the lens capsule; lens material that includes gamma-crystallin (see 123660) is then extruded into the anterior and posterior chambers, leading to congenital ocular inflammation.
In affected members of a consanguineous Pakistani family segregating autosomal recessive corneal opacification, congenital cataract, and microcornea (ASGD7; 269400), originally reported by Khan et al. (2011) (family MEP60), Khan et al. (2011) identified homozygosity for a 1-bp deletion (c.2568delC) in exon 17 of the PXDN gene, causing a frameshift predicted to result in premature termination of the protein (Cys857AlafsTer5) within the heme peroxidase domain. The mutation, which segregated with disease in the family, was not found in 170 ethnically matched controls.
In affected members of a consanguineous Pakistani family (family MEP59) segregating autosomal recessive corneal opacification, congenital cataract, and microcornea (ASGD7; 269400), Khan et al. (2011) identified homozygosity for a c.2638C-T transition in exon 17 of the PXDN gene, resulting in an arg880-to-cys (R880C) substitution at a highly conserved residue within the peroxidase domain. The mutation, which segregated with disease in the family, was not found in 170 ethnically matched controls.
In 4 affected sibs from a consanguineous Cambodian family (family CA) with total corneal opacification and buphthalmos (ASGD7; 269400), Khan et al. (2011) identified homozygosity for a c.1021C-T transition in exon 10 of the PXDN gene, resulting in an arg341-to-ter (R341X) substitution within the Ig-like domain. The mutation segregated with disease in the family and was not found in 58 ethnically matched control chromosomes.
In a brother and sister with ASGD7, Choi et al. (2015) identified compound heterozygosity for the R341X mutation in the PXDN gene, and a 23-bp deletion (c.2375_2397del23; 605158.0004) in the peroxidase domain, causing a frameshift predicted to result in a premature termination codon (Leu792HisfsTer67). Additional features in the 2 sibs included hypotonia and developmental delay; however, it was unclear whether these features were caused by the PXDN mutations, as these manifestations had not been described in other reported patients.
For discussion of the 23-bp deletion in the PXDN gene (c.2375_2397del23) that was found in compound heterozygous state in patients with anterior segment dysgenesis-7 (ASGD7; 269400) by Choi et al. (2015), see 605158.0003.
Cheng, G., Salerno, J. C., Cao, Z., Pagano, P. J., Lambeth, J. D. Identification and characterization of VPO1, a new animal heme-containing peroxidase. Free Radic. Biol. Med. 45: 1682-1694, 2008. [PubMed: 18929642] [Full Text: https://doi.org/10.1016/j.freeradbiomed.2008.09.009]
Choi, A., Lao, R., Ling-Fung Tang, P., Wan, E., Mayer, W., Bardakjian, T., Shaw, G. M., Kwok, P., Schneider, A., Slavotinek, A. Novel mutations in PXDN cause microphthalmia and anterior segment dysgenesis. Europ. J. Hum. Genet. 23: 337-341, 2015. [PubMed: 24939590] [Full Text: https://doi.org/10.1038/ejhg.2014.119]
Horikoshi, N., Cong, J., Kley, N., Shenk, T. Isolation of differentially expressed cDNAs from p53-dependent apoptotic cells: activation of the human homologue of the Drosophila peroxidasin gene. Biochem. Biophys. Res. Commun. 261: 864-869, 1999. [PubMed: 10441517] [Full Text: https://doi.org/10.1006/bbrc.1999.1123]
Khan, K., Al-Maskari, A., McKibbin, M., Carr, I. M., Booth, A., Mohamed, M., Siddiqui, S., Poulter, J. A., Parry, D. A., Logan, C. V., Hashmi, A., Sahi, T., and 9 others. Genetic heterogeneity for recessively inherited congenital cataract microcornea with corneal opacity. Invest. Ophthal. Vis. Sci. 52: 4294-4299, 2011. [PubMed: 21474777] [Full Text: https://doi.org/10.1167/iovs.10-6776]
Khan, K., Rudkin, A., Parry, D. A., Burdon, K. P., McKibbin, M., Logan, C. V., Abdelhamed, Z. I. A., Muecke, J. S., Fernandez-Fuentes, N., Laurie, K. J., Shires, M., Fogarty, R., and 17 others. Homozygous mutations in PXDN cause congenital cataract, corneal opacity, and developmental glaucoma. Am. J. Hum. Genet. 89: 464-473, 2011. [PubMed: 21907015] [Full Text: https://doi.org/10.1016/j.ajhg.2011.08.005]
Nagase, T., Seki, N., Ishikawa, K., Ohira, M., Kawarabayasi, Y., Ohara, O., Tanaka, A., Kotani, H., Miyajima, N., Nomura, N. Prediction of the coding sequences of unidentified human genes. VI. The coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of cDNA clones from cell line KG-1 and brain. DNA Res. 3: 321-329, 1996. [PubMed: 9039502] [Full Text: https://doi.org/10.1093/dnares/3.5.321]
Weiler, S. R., Taylor, S. M., Deans, R. J., Kan-Mitchell, J., Mitchell, M. S., Trent, J. M. Assignment of a human melanoma associated gene MG50 (D2S448) to chromosome 2p25.3 by fluorescence in situ hybridization. Genomics 22: 243-244, 1994. [PubMed: 7959781] [Full Text: https://doi.org/10.1006/geno.1994.1374]
Yan, X., Sabrautzki, S., Horsch, M., Fuchs, H., Gailus-Durner, V., Beckers, J., Hrabe de Angelis, M., Graw, J. Peroxidasin is essential for eye development in the mouse. Hum. Molec. Genet. 23: 5597-5614, 2014. [PubMed: 24895407] [Full Text: https://doi.org/10.1093/hmg/ddu274]