PXDN

Summary

PXDN (peroxidasin, HGNC:14966) is a protein-coding gene on chromosome 2p25.3, encoding Peroxidasin homolog (Q92626). Catalyzes the two-electron oxidation of bromide by hydrogen peroxide and generates hypobromite as a reactive intermediate which mediates the formation of sulfilimine cross-links between methionine and hydroxylysine residues within an uncross-linked collagen IV/COL4A1 NC1 hexamer.

This gene encodes a heme-containing peroxidase that is secreted into the extracellular matrix. It is involved in extracellular matrix formation, and may function in the physiological and pathological fibrogenic response in fibrotic kidney. Mutations in this gene cause corneal opacification and other ocular anomalies, and also microphthalmia and anterior segment dysgenesis.

Source: NCBI Gene 7837 — RefSeq curated summary.

At a glance

• Gene–disease (curated): anterior segment dysgenesis 7 (Definitive, ClinGen)
• GWAS associations: 9
• Clinical variants (ClinVar): 615 total — 19 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 14
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_012293

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14966
Approved symbol	PXDN
Name	peroxidasin
Location	2p25.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0230, PRG2, MG50, D2S448, D2S448E, PXN
Ensembl gene	ENSG00000130508
Ensembl biotype	protein_coding
OMIM	605158
Entrez	7837

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 6 protein_coding_CDS_not_defined, 5 protein_coding, 3 retained_intron, 1 nonsense_mediated_decay

ENST00000252804, ENST00000425171, ENST00000433670, ENST00000447941, ENST00000453308, ENST00000465809, ENST00000467191, ENST00000477093, ENST00000477810, ENST00000478155, ENST00000483018, ENST00000485177, ENST00000493654, ENST00000493779, ENST00000857505

RefSeq mRNA: 1 — MANE Select: NM_012293 NM_012293

CCDS: CCDS46221

Canonical transcript exons

ENST00000252804 — 23 exons

Exon	Start	End
ENSE00000895583	1648172	1649675
ENSE00000895589	1663605	1663763
ENSE00000895591	1664958	1665074
ENSE00000895599	1680193	1680362
ENSE00000895616	1744256	1744515
ENSE00001255385	1631887	1634323
ENSE00001677832	1676927	1677044
ENSE00003459022	1643368	1643576
ENSE00003474764	1660881	1661037
ENSE00003498058	1644618	1644752
ENSE00003523344	1654400	1654508
ENSE00003550422	1693063	1693134
ENSE00003563409	1683656	1683727
ENSE00003567599	1666214	1666486
ENSE00003570116	1687632	1687703
ENSE00003581662	1653628	1653785
ENSE00003592731	1638846	1638978
ENSE00003606853	1635408	1635521
ENSE00003632631	1673643	1673812
ENSE00003649807	1662072	1662184
ENSE00003656558	1684080	1684151
ENSE00003672702	1639302	1639422
ENSE00003673782	1691928	1691999

Expression profiles

Bgee: expression breadth ubiquitous, 265 present calls, max score 98.78.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 61.0018 / max 563.2769, expressed in 1305 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
26661	46.9847	1282
26662	12.2050	1229
26663	1.8120	895

Top tissues by expression

288 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	98.78	gold quality
hair follicle	UBERON:0002073	97.78	gold quality
tendon of biceps brachii	UBERON:0008188	96.98	gold quality
visceral pleura	UBERON:0002401	96.22	gold quality
pleura	UBERON:0000977	95.66	gold quality
parietal pleura	UBERON:0002400	95.29	gold quality
saphenous vein	UBERON:0007318	95.27	gold quality
smooth muscle tissue	UBERON:0001135	94.82	gold quality
cartilage tissue	UBERON:0002418	94.69	gold quality
ascending aorta	UBERON:0001496	94.66	gold quality
thoracic aorta	UBERON:0001515	94.61	gold quality
adipose tissue	UBERON:0001013	94.31	gold quality
connective tissue	UBERON:0002384	94.03	gold quality
decidua	UBERON:0002450	93.89	gold quality
subcutaneous adipose tissue	UBERON:0002190	93.77	gold quality
descending thoracic aorta	UBERON:0002345	93.61	gold quality
right ovary	UBERON:0002118	93.55	gold quality
blood vessel layer	UBERON:0004797	93.50	gold quality
adipose tissue of abdominal region	UBERON:0007808	93.49	gold quality
myometrium	UBERON:0001296	93.26	gold quality
omental fat pad	UBERON:0010414	93.24	gold quality
peritoneum	UBERON:0002358	93.23	gold quality
endometrium epithelium	UBERON:0004811	93.00	gold quality
oocyte	CL:0000023	92.93	gold quality
aorta	UBERON:0000947	92.56	gold quality
pericardium	UBERON:0002407	92.42	gold quality
left ovary	UBERON:0002119	92.35	gold quality
ovary	UBERON:0000992	92.17	gold quality
endometrium	UBERON:0001295	92.06	gold quality
muscle layer of sigmoid colon	UBERON:0035805	91.97	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-GEOD-83139	yes	640.45
E-CURD-11	yes	376.71
E-MTAB-6678	yes	12.92
E-MTAB-5061	yes	11.56
E-CURD-112	yes	7.98
E-ENAD-27	yes	6.80
E-MTAB-6075	no	3.07
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFE2L2, SNAI1

miRNA regulators (miRDB)

145 targeting PXDN, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-98-5P	99.98	72.33	1787
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-548AN	99.97	70.91	2817
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548A-5P	99.94	71.27	3482

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 37)

• peroxidasin secretion represents a previously unknown pathway in extracellular matrix formation with a potentially important role in the physiological and pathological fibrogenic response. (PMID:19590037)
• Vascular peroxidase-1 is rapidly secreted, circulates in plasma, and supports dityrosine cross-linking reactions. (PMID:21798344)
• plays a critical role in ox-LDL-induced endothelial cell apoptosis (PMID:21820048)
• Homozygous mutations in PXDN cause congenital cataract, corneal opacity, and developmental glaucoma. (PMID:21907015)
• Results from this study indicate that the 2p25.3 duplication disrupting PXDN and MYT1L is a potential autism-causing variant in the pedigree reported here and should receive further consideration as a candidate for autism (PMID:22157634)
• VPO1 is likely to participate in host defense, with bactericidal activity mediated through the generation of HOCl. (PMID:22526679)
• studies demonstrate the enzymatic properties and substrate specificity of VPO1 are similar to MPO; however, significantly lower catalytic rate constants of VPO1 relative to MPO suggest the possibility of other physiologic roles for this peroxidase (PMID:22982576)
• MiR-4782-3p inhibited cell proliferation in NSCLC by targeting USP14, ZEB2 and XIAP. (PMID:24556843)
• Peroxidasin is essential for eye development in the mouse. (PMID:24895407)
• Novel mutations in PXDN cause microphthalmia and anterior segment dysgenesis (PMID:24939590)
• Despite sequence homology at the active site and biophysical properties similar to human peroxidases, the catalytic efficiency of bromide oxidation (kcat/KM(app)) of full-length hsPxd01 is rather low but increased upon truncation. (PMID:25713063)
• The catalytic domain of peroxidasin and its immunoglobulin (Ig) domains are required for efficient sulfilimine bond formation. (PMID:26178375)
• Data suggest that VPO1 contributes to oxidation and retention of LDL in vessel walls, and formation foam cells, indicating VPO1 as a novel potential mediator of atherosclerosis. (PMID:27167346)
• VPO1 plays a critical role in asymmetric dimethylarginine production via H2O2-VPO1-hypochlorous acid pathways, which may contribute to endothelial dysfunction in hypertension. (PMID:27475679)
• PC processing of Pxdn is a key regulatory step that contributes to its function and, therefore, supports BM integrity and homeostasis. (PMID:27697841)
• PXDN expression is significantly upregulated in human masticatory mucosa during wound healing (PMID:28005267)
• The kinetic data unravel the substrate specificity and mechanism of halide oxidation of human peroxidasin 1. The heme enzyme is shown to follow the halogenation cycle that is induced by the rapid H2O2-mediated oxidation of the ferric enzyme to the redox intermediate compound I. Chloride cannot act as a two-electron donor of compound I, whereas thiocyanate, iodide, and bromide efficiently restore the ferric state. (PMID:28154175)
• Data indicate that VPO1 plays a critical role in regulating eNOS expression and activity by structural change and de-phosphorylation. VPO1 expression was up-regulated in Ang-treated HUVECs. Knockdown of VPO1 was su ffi cient to attenuate the Ang induced decrease in eNOS expression and activity. Moreover, the e ff ect of VPO1 on eNOS was mainly achieved by HOCl formation. (PMID:28264790)
• Results show that PXDN expression decreases with TGF-beta1 treatment in cervical carcinoma cell lines, and is regulated by the EMT master transcription factor Snai1. This implicates PXDN in cancer development and processes that involve EMT. (PMID:29305973)
• e showed that collagen IV crosslinks remain intact even under strongly hypoxic conditions. Our hypothesis is that during collagen IV network formation PXDN cooperates with a NOX/DUOX-independent H2O2 source that is functional also at very low ambient oxygen levels. (PMID:29573705)
• PXDN might play a promoter role in the proliferation, invasion and migration of ovarian cancer (OC) cells through regulating the activation of PI3K/Akt pathway. Therefore, PXDN might be regarded as a potential target for OC therapy. (PMID:29661721)
• Peroxidasin 1 functions as a pro-angiogenic peroxidase and a modulator of ERK1/2, Akt and FAK signaling in endothelial cells to promote angiogenesis. (PMID:29982533)
• VPO1 is upregulated in abdominal aortic aneurysmal tissues compared with healthy control tissues. (PMID:30371171)
• we conclude that VPO1 is a crucial regulator of cardiac fibrosis after MI by mediating HOCl/Smad2/3 and ERK1/2 signaling pathways, implying a promising therapeutic target in ischemic cardiomyopathy. (PMID:30844643)
• PXDN knockdown followed by proteomic analysis revealed an increase in oxidative stress, mitochondrial dysfunction and gluconeogenesis pathways. (PMID:31234468)
• The C-terminal von Willebrand factor type C module is not required for trimer formation whereas the alpha-helical linker region located between the peroxidase domain and the VWC is crucial for trimerization. Further, peroxidasin oligomerization occurs intracellularly before C-terminal cleavage. For the first time we present overall solution structures of monomeric and trimeric truncated peroxidasin variants. (PMID:31295557)
• This study presents for the first time transient kinetic measurements of the reactivity of human peroxidasin 1 compound I and compound II with the endogenous one-electron donors nitrite, ascorbate, urate, tyrosine and serotonin using the sequential stopped-flow technique. (PMID:31953133)
• Novel PXDN biallelic variants in patients with microphthalmia and anterior segment dysgenesis. (PMID:32015378)
• The leucine-rich repeat domain of human peroxidasin 1 promotes binding to laminin in basement membranes. (PMID:32485152)
• Peroxidan Plays a Tumor-Promoting Role in Oral Squamous Cell Carcinoma. (PMID:32751434)
• Vascular peroxidase 1 is independently associated with worse kidney function in patients with peripheral artery disease. (PMID:32813143)
• PXDN reduces autophagic flux in insulin-resistant cardiomyocytes via modulating FoxO1. (PMID:33903591)
• Novel heterozygous variants in PXDN cause different anterior segment dysgenesis phenotypes in monozygotic twins. (PMID:33985410)
• Peroxidasin Deficiency Re-programs Macrophages Toward Pro-fibrolysis Function and Promotes Collagen Resolution in Liver. (PMID:35093588)
• Differential DNA methylation analysis of SUMF2, ADAMTS5, and PXDN provides novel insights into colorectal cancer prognosis prediction in Taiwan. (PMID:35317099)
• The role of peroxidasin in solid cancer progression. (PMID:37801286)
• DNA Methylation of PXDN Is Associated with Early-Life Adversity in Adult Mental Disorders. (PMID:39199364)

Cross-species orthologs

11 orthologs

Organism	Symbol	Gene ID
danio_rerio	pxdn	ENSDARG00000098733
mus_musculus	Pxdn	ENSMUSG00000020674
rattus_norvegicus	Pxdn	ENSRNOG00000060614
drosophila_melanogaster	Pxd	FBGN0004577
drosophila_melanogaster	Pxn	FBGN0011828
drosophila_melanogaster	CG4009	FBGN0038469
drosophila_melanogaster	cysu	FBGN0038511
caenorhabditis_elegans		WBGENE00004256
caenorhabditis_elegans		WBGENE00004257
caenorhabditis_elegans		WBGENE00016700
caenorhabditis_elegans		WBGENE00019613

Paralogs (5): MPO (ENSG00000005381), TPO (ENSG00000115705), EPX (ENSG00000121053), PXDNL (ENSG00000147485), LPO (ENSG00000167419)

Protein

Protein identifiers

Peroxidasin homolog — Q92626 (reviewed: Q92626)

Alternative names: Melanoma-associated antigen MG50, Peroxidasin 1, Vascular peroxidase 1, p53-responsive gene 2 protein

All UniProt accessions (5): C9J4I9, Q92626, H7C1W1, H7C300, H7C3W2

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the two-electron oxidation of bromide by hydrogen peroxide and generates hypobromite as a reactive intermediate which mediates the formation of sulfilimine cross-links between methionine and hydroxylysine residues within an uncross-linked collagen IV/COL4A1 NC1 hexamer. In turns, directly contributes to the collagen IV network-dependent fibronectin/FN and laminin assembly, which is required for full extracellular matrix (ECM)-mediated signaling. Thus, sulfilimine cross-links are essential for growth factor-induced cell proliferation and survival in endothelial cells, an event essential to basement membrane integrity. In addition, through the bromide oxidation, may promote tubulogenesis and induce angiogenesis through ERK1/2, Akt, and FAK pathways. Moreover brominates alpha2 collagen IV chain/COL4A2 at ‘Tyr-1485’ and leads to bromine enrichment of the basement membranes. In vitro, can also catalyze the two-electron oxidation of thiocyanate and iodide and these two substrates could effectively compete with bromide and thus inhibit the formation of sulfilimine bonds. Binds laminins. May play a role in the organization of eyeball structure and lens development during eye development.

Subunit / interactions. Homotrimer; disulfide-linked. The homotrimer form is predominant. Homooligomer; disulfide-linked. Oligomerization occurs intracellularly before C-terminal proteolytic cleavage. Interacts with PXDNL; this interaction inhibits the peroxidase activity of PXDN.

Subcellular location. Secreted. Extracellular space. Extracellular matrix. Endoplasmic reticulum. Cell surface. Basement membrane Secreted.

Tissue specificity. Expressed at higher levels in heart, lung, ovary, spleen, intestine and placenta, and at lower levels in liver, colon, pancreas, kidney, thymus, skeletal muscle and prostate. Expressed in tumors such as melanoma, breast cancer, ovarian cancer and glioblastoma. A shorter form probably lacking the signal sequence is found in testis and in EB1 cells undergoing p53/TP53-dependent apoptosis.

Post-translational modifications. Glycosylated. Four sites are completely N-glycosylated (Asn-640, Asn-731, Asn-865 and Asn-1425), whereas the others are found partially glycosylated. Processed by FURIN and the proteolytic processing largely depends on the peroxidase activity of PXDN. The proteolytic cleavage occurs after intracellular homotrimerization and releases into the extracellular matrix a large, catalytically active fragment and a smaller fragment consisting primarily of the C-terminal VWFC domain. The processing enhances both peroxidase activity and sulfilimine cross-links formation.

Disease relevance. Anterior segment dysgenesis 7 (ASGD7) [MIM:269400] A form of anterior segment dysgenesis, a group of defects affecting anterior structures of the eye including cornea, iris, lens, trabecular meshwork, and Schlemm canal. Anterior segment dysgeneses result from abnormal migration or differentiation of the neural crest derived mesenchymal cells that give rise to components of the anterior chamber during eye development. Different anterior segment anomalies may exist alone or in combination, including iris hypoplasia, enlarged or reduced corneal diameter, corneal vascularization and opacity, posterior embryotoxon, corectopia, polycoria, abnormal iridocorneal angle, ectopia lentis, and anterior synechiae between the iris and posterior corneal surface. Clinical conditions falling within the phenotypic spectrum of anterior segment dysgeneses include aniridia, Axenfeld anomaly, Reiger anomaly/syndrome, Peters anomaly, and iridogoniodysgenesis. ASGD7 is an autosomal recessive disease. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. The hypobromous acid formation is activated by increasing nitrite concentrations and inhibited by increasing urate concentrations.

Cofactor. Binds 1 Ca(2+) ion per subunit. Binds 1 heme b (iron(II)-protoporphyrin IX) group covalently per subunit.

Domain organisation. The VWFC domain mediates the covalent links between monomers through disulfide bridges. Ig-like C2-type domains are required to sulfilimine bond formation. The VWFC domain is not required for trimerization. The LRR domain mediates high affinity binding to laminin-1.

Induction. By TGFB1 in fibroblasts and up-regulated in apoptotic cells.

Similarity. Belongs to the peroxidase family. XPO subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q92626-1	1	yes
Q92626-2	2

RefSeq proteins (1): NP_036425* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000483	Cys-rich_flank_reg_C	Domain
IPR001007	VWF_dom	Domain
IPR001611	Leu-rich_rpt	Repeat
IPR003591	Leu-rich_rpt_typical-subtyp	Repeat
IPR003598	Ig_sub2	Domain
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR010255	Haem_peroxidase_sf	Homologous_superfamily
IPR013098	Ig_I-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR019791	Haem_peroxidase_animal	Family
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR034824	Peroxidasin_peroxidase	Domain
IPR034828	Peroxidasin_Ig-like4	Domain
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR037120	Haem_peroxidase_sf_animal	Homologous_superfamily
IPR047018	Peroxidasin_Ig-like3	Domain

Pfam: PF00560, PF03098, PF07679, PF13855, PF23334

Enzyme classification (BRENDA):

• EC 1.11.1.7 — peroxidase (BRENDA: 115 organisms, 442 substrates, 319 inhibitors, 337 Km, 97 kcat entries)

Substrate kinetics (BRENDA)

80 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
H2O2	0.004–30	90
GUAIACOL	0.0006–98.61	55
2,2’-AZINOBIS(3-ETHYLBENZTHIAZOLINE-6-SULFONIC A	0.16–5.4	12
O-DIANISIDINE	0.137–12.56	11
2,2’-AZINO-BIS-(3-ETHYLBENZTHIAZOLE-6-SULFONIC A	0.023–1.6	10
O-PHENYLENEDIAMINE	0.38–9	9
3,3’,5,5’-TETRAMETHYLBENZIDINE	0.045–0.2	8
FERULIC ACID	0.01–1.5	8
CAFFEIC ACID	0.08–1.9	7
CHLOROGENIC ACID	0.15–0.64	7
PYROGALLOL	0.29–55.4	7
MN2+	0.11–0.351	6
ESCULETIN	0.0052–2	5
2,2’-AZINO-BIS(3-ETHYLBENZTHIAZOLE-6-SULFONIC AC	0.036–10.4	4
PHENOL	1.12–9.45	4

Catalyzed reactions (Rhea), 5 shown:

• bromide + H2O2 = hypobromite + H2O (RHEA:66016)
• L-lysyl-[collagen] + L-methionyl-[collagen] + H2O2 = [collagen]-L-lysyl-N-S-L-methionyl-[collagen] + 2 H2O + H(+) (RHEA:66020)
• L-lysyl-[collagen] + L-methionyl-[collagen] + hypobromite = [collagen]-L-lysyl-N-S-L-methionyl-[collagen] + bromide + H2O + H(+) (RHEA:66024)
• hypobromite + L-tyrosyl-[protein] + H(+) = 3-bromo-L-tyrosyl-[protein] + H2O (RHEA:69356)
• L-tyrosyl-[protein] + bromide + H2O2 + H(+) = 3-bromo-L-tyrosyl-[protein] + 2 H2O (RHEA:69360)

UniProt features (75 total): disulfide bond 17, glycosylation site 10, mutagenesis site 9, repeat 8, binding site 8, domain 7, sequence variant 3, chain 2, region of interest 2, site 2, modified residue 2, splice variant 2, signal peptide 1, compositionally biased region 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92626-F1	80.43	0.38

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (3): 827 (proton acceptor); 977 (transition state stabilizer); 1336 (cleavage; by furin)

Ligand- & substrate-binding residues (8): 826 (covalent); 828; 907; 909; 911; 913; 980 (covalent); 1074 (axial binding residue)

Post-translational modifications (2): 1176, 1180

Disulfide bonds (17): 36–42, 40–49, 196–243, 198–222, 267–317, 363–412, 454–502, 546–594, 723–885, 732–748, 736, 847–857, 851–875, 959–970, 1177–1234, 1275–1301, 1315

Glycosylation sites (10): 640, 699, 719, 731, 865, 964, 1178, 1280, 1368, 1425

Mutagenesis-validated functional residues (9):

Position	Phenotype
736	loss of protein homooligomerization. loss of protein homooligomerization; when associated with s-1315. does not affect p
823	loss of bromide oxidation. loss of tubulogenesis. does not induce angiogenesis.
823	loss of peroxidase activity. does not affect oligomerization. loss of peroxidase activity; when associated with e-826. d
826	loss of peroxidase activity. does not affect oligomerization. loss of peroxidase activity; when associated with e-823. d
1315	loss of protein homooligomerization. loss of protein homooligomerization; when associated with s-1316 and s-1319. loss o
1316	does not affect protein homooligomerization. loss of protein homooligomerization; when associated with s-1315 and s-1319
1319	does not affect protein homooligomerization. loss of protein homooligomerization; when associated with s-1315 and s-1316
1335–1336	loss of proteolytic cleavage. decreases the formation of sulfilimine cross-links in collagen iv. reduces the proteolytic
1354–1355	does not affect the proteolytic processing.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-2243919	Crosslinking of collagen fibrils
R-HSA-9926550	Regulation of MITF-M-dependent genes involved in extracellular matrix, focal adhesion and epithelial-to-mesenchymal transition

MSigDB gene sets: 740 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, GSE45365_NK_CELL_VS_CD8_TCELL_UP, VERHAAK_AML_WITH_NPM1_MUTATED_DN, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, chr2p25, GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, REACTOME_INNATE_IMMUNE_SYSTEM, REACTOME_GAB1_SIGNALOSOME, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_COLLAGEN_FIBRIL_ORGANIZATION, GOBP_RESPONSE_TO_PEPTIDE, GOCC_SECRETORY_GRANULE, GOBP_HYDROGEN_PEROXIDE_CATABOLIC_PROCESS

GO Biological Process (15): angiogenesis (GO:0001525), eye development (GO:0001654), immune response (GO:0006955), response to oxidative stress (GO:0006979), cell adhesion (GO:0007155), extracellular matrix organization (GO:0030198), collagen fibril organization (GO:0030199), hydrogen peroxide catabolic process (GO:0042744), protein homooligomerization (GO:0051260), protein homotrimerization (GO:0070207), basement membrane assembly (GO:0070831), basement membrane organization (GO:0071711), negative regulation of cytokine-mediated signaling pathway (GO:0001960), system development (GO:0048731), cellular oxidant detoxification (GO:0098869)

GO Molecular Function (10): peroxidase activity (GO:0004601), interleukin-1 receptor antagonist activity (GO:0005152), extracellular matrix structural constituent (GO:0005201), oxidoreductase activity, acting on peroxide as acceptor (GO:0016684), heme binding (GO:0020037), laminin-1 binding (GO:0043237), metal ion binding (GO:0046872), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), lactoperoxidase activity (GO:0140825)

GO Cellular Component (7): extracellular region (GO:0005576), basement membrane (GO:0005604), obsolete extracellular space (GO:0005615), endoplasmic reticulum (GO:0005783), cell surface (GO:0009986), extracellular matrix (GO:0031012), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Assembly of collagen fibrils and other multimeric structures	1
MITF-M-dependent gene expression	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
extracellular matrix organization	2
extracellular matrix	2
cellular anatomical structure	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
sensory organ development	1
visual system development	1
immune system process	1
response to stimulus	1
response to stress	1
cellular process	1
extracellular structure organization	1
external encapsulating structure organization	1
catabolic process	1
hydrogen peroxide metabolic process	1
protein complex oligomerization	1
protein homooligomerization	1
protein trimerization	1
basement membrane organization	1
extracellular matrix assembly	1
regulation of cytokine-mediated signaling pathway	1
negative regulation of signal transduction	1
cytokine-mediated signaling pathway	1
negative regulation of response to cytokine stimulus	1
multicellular organism development	1
anatomical structure development	1
cellular detoxification	1
antioxidant activity	1
oxidoreductase activity, acting on peroxide as acceptor	1
negative regulation of cytokine-mediated signaling pathway	1
cytokine receptor binding	1
interleukin-1 binding	1
receptor antagonist activity	1
structural molecule activity	1
oxidoreductase activity	1
tetrapyrrole binding	1
laminin binding	1
cation binding	1
binding	1
catalytic activity	1

Protein interactions and networks

STRING

9710 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PXDN	PXDNL	A1KZ92	981
PXDN	ALB	P02768	936
PXDN	ACTB	P02570	925
PXDN	GAPDH	P00354	924
PXDN	CASP3	P42574	918
PXDN	CYCS	P00001	889
PXDN	ANXA5	P08758	886
PXDN	AKT1	P31749	873
PXDN	CCK	P06307	855
PXDN	MAPK3	P27361	846
PXDN	BCL2	P10415	845
PXDN	EGF	P01133	830
PXDN	FN1	P02751	826
PXDN	STAT3	P40763	824
PXDN	TP53	P04637	819

IntAct

105 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
FBXO6	MAN2B1	psi-mi:“MI:0914”(association)	0.640
FGL1	LCMT2	psi-mi:“MI:0914”(association)	0.640
CFTR	HAX1	psi-mi:“MI:0914”(association)	0.610
ERP44	MEX3A	psi-mi:“MI:0914”(association)	0.530
DEFA1	MANBA	psi-mi:“MI:0914”(association)	0.530
HAUS1	BET1	psi-mi:“MI:0914”(association)	0.530
CNPY3	SELENOT	psi-mi:“MI:0914”(association)	0.530
CENPK	DHRS12	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
PLAUR	XRCC3	psi-mi:“MI:0914”(association)	0.530
CNPY3	LRIG2	psi-mi:“MI:0914”(association)	0.530
NOTCH2	ZNF316	psi-mi:“MI:0914”(association)	0.530
PLOD3	PLOD2	psi-mi:“MI:0914”(association)	0.530
ACADSB	PXDN	psi-mi:“MI:0915”(physical association)	0.400
PLA2G12A	PXDN	psi-mi:“MI:0915”(physical association)	0.400
PXDN	BNIPL	psi-mi:“MI:0915”(physical association)	0.370
FBXO6	GNS	psi-mi:“MI:0914”(association)	0.350
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
SCGB2A2	GXYLT2	psi-mi:“MI:0914”(association)	0.350
PLAUR	DDX11L8	psi-mi:“MI:0914”(association)	0.350

BioGRID (100): PXDN (Affinity Capture-MS), PXDN (Affinity Capture-MS), PXDN (Affinity Capture-MS), PXDN (Affinity Capture-MS), PXDN (Affinity Capture-MS), PXDN (Affinity Capture-MS), PXDN (Affinity Capture-MS), SPTAN1 (Co-fractionation), PXDN (Affinity Capture-MS), PXDN (Affinity Capture-MS), PXDN (Affinity Capture-MS), PXDN (Affinity Capture-MS), PXDN (Affinity Capture-MS), PXDN (Affinity Capture-MS), PXDN (Affinity Capture-MS)

ESM2 similar proteins: A4IGL7, D3ZB51, E9PZ19, O75882, O94779, O95970, P00533, P02469, P07942, P13590, P15209, P24503, P24786, P33150, P39038, P55245, P55283, P68500, P97300, P97527, P97546, Q01279, Q01973, Q03351, Q16288, Q16620, Q1EGL2, Q3B7N0, Q3UQ28, Q5IFJ9, Q5IS37, Q5IS82, Q5R945, Q63604, Q6IS24, Q6VNS1, Q7TPD3, Q7TT15, Q8K4Y5, Q8N475

Diamond homologs: A0A087WV53, A2AAJ9, A2ASS6, A2RUH7, O75147, O94856, O94898, P05548, P52179, P54296, P97685, Q00872, Q23551, Q52KR2, Q5VST9, Q62234, Q80W87, Q810U3, Q8WX93, Q92626, A0A1Y9G8H0, A0A452E9Y6, A1KZ92, A4IGL7, A5JUY8, B3A0P3, B3A0Q8, G5EG78, H2A0M7, O61213, P09933, P11247, P11678, P22079, P80025, P82600, P90820, Q01603, Q20616, Q23490

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
NFE2L2	“up-regulates quantity by expression”	PXDN	“transcriptional regulation”
SNAI1	“down-regulates quantity by repression”	PXDN	“transcriptional regulation”
PXDN	“up-regulates quantity by stabilization”	COL4A4	“catalytic activity”
PXDN	up-regulates	Epithelial-mesenchymal_transition

Disease & clinical

Clinical variants and AI predictions

ClinVar

615 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	19
Likely pathogenic	9
Uncertain significance	250
Likely benign	198
Benign	93

Top pathogenic / likely-pathogenic (28)

Variant ID	HGVS	Classification
1074765	NM_012293.3(PXDN):c.2350del (p.His784fs)	Pathogenic
1342666	NM_012293.3(PXDN):c.1109del (p.Pro370fs)	Pathogenic
1399091	NM_012293.3(PXDN):c.2824C>T (p.Gln942Ter)	Pathogenic
140741	NM_012293.3(PXDN):c.2568del (p.Cys857fs)	Pathogenic
140742	NM_012293.3(PXDN):c.2638C>T (p.Arg880Cys)	Pathogenic
140743	NM_012293.3(PXDN):c.1021C>T (p.Arg341Ter)	Pathogenic
140744	NM_012293.3(PXDN):c.2375_2397del (p.Leu792fs)	Pathogenic
2015134	NM_012293.3(PXDN):c.1927C>T (p.Arg643Ter)	Pathogenic
2156476	NM_012293.3(PXDN):c.2353C>T (p.Arg785Ter)	Pathogenic
2628023	NM_012293.3(PXDN):c.1838-2A>G	Pathogenic
3064201	NM_012293.3(PXDN):c.3609-1G>C	Pathogenic
3610735	NM_012293.3(PXDN):c.2568dup (p.Cys857fs)	Pathogenic
694375	NM_012293.3(PXDN):c.2276C>T (p.Ser759Leu)	Pathogenic
694376	NM_012293.3(PXDN):c.4216_4225dup (p.Arg1409delinsProTer)	Pathogenic
694377	NM_012293.3(PXDN):c.2569del (p.Cys857fs)	Pathogenic
694378	NM_012293.3(PXDN):c.693_697dup (p.Val233fs)	Pathogenic
694379	NM_012293.3(PXDN):c.1A>G (p.Met1Val)	Pathogenic
932291	NM_012293.3(PXDN):c.4085_4086del (p.Gln1362fs)	Pathogenic
984974	NM_012293.3(PXDN):c.2098G>T (p.Gly700Ter)	Pathogenic
152339	GRCh38/hg38 2p25.3(chr2:12770-2310816)x1	Likely pathogenic
2432899	NM_012293.3(PXDN):c.3743+2T>G	Likely pathogenic
2629971	NM_012293.3(PXDN):c.3730C>T (p.Arg1244Ter)	Likely pathogenic
3064154	NM_012293.3(PXDN):c.1018+1G>A	Likely pathogenic
3255593	NM_012293.3(PXDN):c.3355_3356del (p.Arg1119fs)	Likely pathogenic
3362525	NM_012293.3(PXDN):c.3964del (p.Arg1322fs)	Likely pathogenic
3911881	NM_012293.3(PXDN):c.3790C>T (p.Gln1264Ter)	Likely pathogenic
4846916	NM_012293.3(PXDN):c.20del (p.Gly7fs)	Likely pathogenic
635164	NM_012293.3(PXDN):c.2459A>G (p.Gln820Arg)	Likely pathogenic

SpliceAI

9164 predictions. Top by Δscore:

Variant	Effect	Δscore
11:57387534:C:CC	acceptor_gain	1.0000
11:57387864:CC:C	acceptor_gain	1.0000
11:57387865:CC:C	acceptor_gain	1.0000
11:57387975:C:A	donor_gain	1.0000
11:57388704:GTAAA:G	acceptor_gain	1.0000
11:57388709:C:CC	acceptor_gain	1.0000
11:57389883:TTA:T	donor_loss	1.0000
11:57389884:TA:T	donor_loss	1.0000
11:57389885:A:AC	donor_gain	1.0000
11:57389885:AC:A	donor_loss	1.0000
11:57389886:C:CA	donor_gain	1.0000
11:57389886:C:CC	donor_gain	1.0000
11:57389886:CT:C	donor_gain	1.0000
11:57389886:CTT:C	donor_gain	1.0000
11:57389886:CTTA:C	donor_gain	1.0000
11:57389886:CTTAG:C	donor_gain	1.0000
11:57389890:G:C	donor_gain	1.0000
11:57389955:TC:T	acceptor_gain	1.0000
11:57389956:CC:C	acceptor_gain	1.0000
11:57389957:C:CC	acceptor_gain	1.0000
11:57389957:CTGC:C	acceptor_loss	1.0000
11:57389958:T:A	acceptor_loss	1.0000
12:120212576:CATTC:C	acceptor_gain	1.0000
12:120212577:ATTC:A	acceptor_gain	1.0000
12:120212578:TTC:T	acceptor_gain	1.0000
12:120212579:TC:T	acceptor_gain	1.0000
12:120212580:CC:C	acceptor_gain	1.0000
12:120212581:C:CC	acceptor_gain	1.0000
12:120212585:C:CT	acceptor_gain	1.0000
12:120213836:CCTTA:C	donor_loss	1.0000

AlphaMissense

9722 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:1662078:C:A	W558C	1.000
2:1662078:C:G	W558C	1.000
2:1662079:C:G	W558S	1.000
2:1662080:A:G	W558R	1.000
2:1662080:A:T	W558R	1.000
2:1664968:C:A	W466C	1.000
2:1664968:C:G	W466C	1.000
2:1664970:A:G	W466R	1.000
2:1664970:A:T	W466R	1.000
2:1666380:C:A	W375C	1.000
2:1666380:C:G	W375C	1.000
2:1676938:C:A	W279C	1.000
2:1676938:C:G	W279C	1.000
2:1676940:A:G	W279R	1.000
2:1676940:A:T	W279R	1.000
2:1687632:A:G	L139P	1.000
2:1649512:C:A	W756C	0.999
2:1649512:C:G	W756C	0.999
2:1654442:A:T	V635D	0.999
2:1654455:C:G	A631P	0.999
2:1660924:G:C	N598K	0.999
2:1660924:G:T	N598K	0.999
2:1660936:A:C	C594W	0.999
2:1660937:C:G	C594S	0.999
2:1660938:A:G	C594R	0.999
2:1660938:A:T	C594S	0.999
2:1660944:A:C	Y592D	0.999
2:1660982:A:G	L579S	0.999
2:1663622:A:G	L517P	0.999
2:1663654:G:C	N506K	0.999

dbSNP variants (sampled 300 via entrez): RS1000004258 (2:1639209 C>A,G), RS1000005723 (2:1713965 C>A,T), RS1000034 (2:1653807 G>A), RS1000035 (2:1654072 G>A), RS1000068330 (2:1674056 T>C), RS1000150214 (2:1722641 C>T), RS1000259753 (2:1633731 G>A), RS1000269325 (2:1652298 A>T), RS1000275749 (2:1686449 A>G), RS1000279839 (2:1727710 C>A), RS1000327714 (2:1646780 C>A), RS1000344605 (2:1733457 C>T), RS1000371636 (2:1725905 A>G), RS1000378326 (2:1647023 T>C), RS1000423941 (2:1726125 A>G)

Disease associations

OMIM: gene MIM:605158 | disease phenotypes: MIM:269400, MIM:231300, MIM:107250

GenCC curated gene-disease

Disease	Classification	Inheritance
anterior segment dysgenesis 7	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
anterior segment dysgenesis 7	Definitive	AR

Mondo (3): anterior segment dysgenesis 7 (MONDO:0010015), glaucoma 3A (MONDO:0009277), anterior segment dysgenesis (MONDO:0019503)

Orphanet (4): Congenital cataract microcornea with corneal opacity (Orphanet:289499), Congenital glaucoma (Orphanet:98976), Juvenile glaucoma (Orphanet:98977), Anterior segment developmental anomaly (Orphanet:88632)

HPO phenotypes

14 total (14 of 14 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000482	Microcornea
HP:0000518	Cataract
HP:0000557	Buphthalmos
HP:0000568	Microphthalmia
HP:0000612	Iris coloboma
HP:0000647	Sclerocornea
HP:0003577	Congenital onset
HP:0003623	Neonatal onset
HP:0007663	Reduced visual acuity
HP:0007700	Ocular anterior segment dysgenesis
HP:0007906	Ocular hypertension
HP:0007957	Corneal opacity
HP:0011483	Anterior synechiae of the anterior chamber

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST004125_15	Type 2 diabetes (age of onset)	3.000000e-06
GCST006195_82	Systolic blood pressure x smoking status (current vs non-current) interaction (2df test)	1.000000e-09
GCST006218_87	Erosive tooth wear (severe vs non-severe)	4.000000e-08
GCST006226_12	Erosive tooth wear (severe vs none or mild)	5.000000e-06
GCST006493_7	Systemic sclerosis	6.000000e-06
GCST006585_1861	Blood protein levels	2.000000e-11
GCST008839_77	Height	5.000000e-17
GCST010002_382	Refractive error	6.000000e-25
GCST012033_6	Sleep (1/3-day periodicity)	4.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure
EFO:0006527	smoking status measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

66 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases expression, increases methylation	4
sodium arsenite	decreases expression, increases expression	3
Tobacco Smoke Pollution	affects expression, decreases expression	3
Arsenic	affects cotreatment, decreases expression	2
Cisplatin	affects response to substance, affects cotreatment, increases expression	2
Particulate Matter	decreases expression, increases abundance, affects expression, increases reaction	2
aristolochic acid I	decreases expression	1
testosterone enanthate	affects expression	1
propionaldehyde	increases expression	1
bisphenol A	increases expression	1
sodium arsenate	decreases expression	1
decabromobiphenyl ether	decreases expression	1
beta-lapachone	decreases expression	1
mono-(2-ethylhexyl)phthalate	increases abundance, increases methylation	1
W 7	decreases reaction, increases expression	1
cobaltous chloride	decreases secretion	1
cerous chloride	affects cotreatment, decreases expression	1
potassium chromate(VI)	increases expression	1
lanthanum chloride	affects cotreatment, decreases expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
CGP 52608	affects binding, increases reaction	1
chloropicrin	decreases expression	1
monomethylarsonous acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine	affects expression, increases reaction	1
nutlin 3	affects cotreatment, increases secretion	1
ICG 001	decreases expression	1
abrine	decreases expression	1
MRK 003	decreases expression	1
bisphenol S	increases expression	1

Clinical trials (associated diseases)

1 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05641103	Not specified	COMPLETED	PREDIGA 2: Spanish Acronym of Educational and Diagnostic Project for Gaucher and ASMD