PXDN

protein-coding

peroxidasin, the group of I-set domain containing

Gene summary

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. [provided by RefSeq, Aug 2014]

MANE transcript

NM_012293.3

Inheritance

ClinVar variants

P:31U:274B:164

Top phenotype

Anterior segment dysgenesis 7

gnomAD constraint

pLI —, LoF o/e 0.37

Max pathogenic AF

—

Genomic locus

chr2:1,631,887-1,744,852

External References & Databases

Ensembl (ENSG00000130508)

Transcript & Mutation Effects

hg38 • Region Span ~113.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

anterior segment dysgenesis 7STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010015

Submitter: G2P

anterior segment dysgenesis 7STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010015

Submitter: PanelApp Australia

anterior segment dysgenesis 7MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0010015

Submitter: Ambry Genetics

anterior segment dysgenesis 7STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010015

Submitter: Labcorp Genetics (formerly Invitae)

anterior segment dysgenesis 7SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010015

Submitter: Orphanet

anterior segment dysgenesis 7DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010015

Submitter: ClinGen

The relationship between **PXDN** and anterior segment dysgenesis 7 (ASD7), an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of June 15, 2023. **PXDN** encodes a heme-containing peroxidase that is secreted into the extracellular matrix (ECM). It catalyzes the formation of the sulfilimine bond between methionine and hydroxylysine in Collagen IV, which may be necessary to reinforce the mechanical strength of ECM and maintain tissue integrity (PMID: 31817535). ASD7 is also associated with partial or total corneal opacification, microcornea, microphthalmia, cataract in humans. **PXDN** was first reported in relation to autosomal recessive ASD7 in 2011 (Khan et al, 2011, PMID: 21907015). At least 15 nonsense, frameshift, and missense variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data (12 points): Variants in this gene have been reported in at least 9 probands in 4 publications (PMID: 32499604, 35595447, 32015378, 21907015). Variants in this gene segregated with disease in 8 additional family members. The mechanism for disease is biallelic loss of function. Summary of experimental data (3 points): This gene-disease association is supported by animal models. **PXDN** is expressed in the corneal epithelial layer, lens epithelium in the adult mouse eye (PMID: 21907015). Two homozygous knock out mouse models of **Pxdn** recapitulate the human phenotype. An ENU-induced knock-out of **Pxdn** due to a nonsense variant in exon 17 leads to anterior segment dysgenesis in mice (PMID: 24895407). CRISPR-mediated knock-out of **Pxdn** in mice leads to severe defects in eye morphology including absence of lenses, eyelids and disorganized retinal structures (PMID: 31817535). In summary, **PXDN** is definitively associated with autosomal recessive ASD7. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Glaucoma and Neuro-Ophthalmology GCEP on June 15th, 2023.

Clinical Genomic Database (CGD)

Anterior segment dysgenesis 7AR

Manifestation: Ophthalmologic

Intervention: Ophthalmologic

Rationale: Some individual are at risk of glaucoma, and surveillance and early treatment may be beneficial; Agents that may contribute to glaucoma should be avoided

Refs: 21907015; 24939590

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PXDN variants in ClinVar

9 Conditions Cataloged

Anterior segment dysgenesis 7Total: 241

Inborn genetic diseasesTotal: 202

not providedTotal: 171

not specifiedTotal: 55

PXDN-related disorderTotal: 39

Anterior segment dysgenesisTotal: 2

EBV-positive nodal T- and NK-cell lymphomaTotal: 1

Glaucoma 3ATotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_012293.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	123 clinvar	14 clinvar	140
missense	2 clinvar	1 clinvar	265 clinvar	22 clinvar	5 clinvar	295
nonsense	6 clinvar	2 clinvar				8
start loss	1 clinvar					1
frameshift	9 clinvar	6 clinvar				15
splice donor/acceptor (+/-2bp)	2 clinvar	2 clinvar	6 clinvar			10
Total	20	11	274	145	19	469

Highest pathogenic variant AF is 0.000014563981

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 19 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_012293.3	RefSeq	NP_036425.1	23	MANE Select
ENST00000252804.9	Ensembl	ENSP00000252804.4	23	MANE Select
ENST00000425171.2	Ensembl	ENSP00000398363.2	16	Standard
ENST00000425171.3	Ensembl	ENSP00000398363.2	16	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
pxdn	Danio rerio	Structure: trunk Quality: curved dorsal abnormal

Gene / Model

Organism

Observed Phenotype

pxdn

Danio rerio

Structure: trunk

Quality: curved dorsal

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

miR-targeted genes in epithelium - TarBase
miR-targeted genes in lymphocytes - TarBase
miR-targeted genes in muscle cell - TarBase
miR-targeted genes in squamous cell - TarBase
EGF-EGFR Signaling Pathway

Biological Process

negative regulation of cytokine-mediated signaling pathway
immune response
response to oxidative stress
extracellular matrix organization
hydrogen peroxide catabolic process

Molecular Function

peroxidase activity
interleukin-1 receptor antagonist activity
extracellular matrix structural constituent
heme binding
metal ion binding

Cellular Component

extracellular region
extracellular space
endoplasmic reticulum
collagen-containing extracellular matrix
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000252804
Coding exons: 23
Length: 112966
Individuals with no LoFs: 124669
Homozygous LoFs: 0
Heterozygous LoFs: 41
Defined: 124710
p: 0.000164

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.21	752	943	0.798	0.0000658	9601
Missense (PolyPhen)		227	347.29	0.65364		3585
Synonymous	-1.69	465	421	1.10	0.0000345	2969
Loss of Function	4.62	23	62.3	0.369	0.00000325	673

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000065	0.000064	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00022	0.00022	rare
Finnish	0.000093	0.000093	rare
European (Non-Finnish)	0.00023	0.00023	rare
South Asian	0.00020	0.00020	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Displays low peroxidase activity and is likely to participate in H(2)O(2) metabolism and peroxidative reactions in the cardiovascular system. Plays a role in extracellular matrix formation. {ECO:0000269|PubMed:18929642, ECO:0000269|PubMed:19590037}.;
Disease: DISEASE: 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. {ECO:0000269|PubMed:21907015}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.103

Intolerance Scores

RVIS EVS: -1.51
RVIS percentile EVS: 3.48

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.267

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium