PAX2
protein-codingpaired box 2, the group of Paired boxes|PRD class homeoboxes and pseudogenes
Gene summary
PAX2 encodes paired box gene 2, one of many human homologues of the Drosophila melanogaster gene prd. The central feature of this transcription factor gene family is the conserved DNA-binding paired box domain. PAX2 is believed to be a target of transcriptional supression by the tumor suppressor gene WT1. Mutations within PAX2 have been shown to result in optic nerve colobomas and renal hypoplasia. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Dec 2014]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~94.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0007352
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0007352
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0007352
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0019006
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007352
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0014451
Submitter: ClinGen
The *PAX2* gene is located on chromosome 10 at 10q24.31 and encodes the protein paired box gene 2, which is a transcription factor involved in the development of the urogenital tract, eyes, and central nervous system (CNS). *PAX2* mutation was first reported in relation to autosomal dominant papillorenal syndrome in 1995 (Sanyanusin et al., PMID: 7795640). Papillorenal syndrome is characterized by congenital anomalies of kidney and urinary tract (CAKUT), ocular anomalies and high frequency hearing loss. *PAX2* mutation has also been reported in association with Focal segmental glomerulosclerosis 7 (first report: Barua et al., PMID: 24676634), characterized by significant protein loss in the urine causing generalized edema. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism and inheritance pattern, and both disease entities have significant phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity, papillorenal syndrome (OMIM:120330) and focal segmental glomerulosclerosis 7 (OMIM:616002). The preferred disease name suggested for this grouping of disorders is ‘Nephropathy, with or without extra-renal features - *PAX2*’. Sixteen variants (frameshift, nonsense, in-frame insertion, missense, and splice) that have been reported in 18 probands in four publications (PMIDs: 7795640, 9106533, 24676634, 22213154) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is proposed to be loss of function in DNA binding domains of PAX2. This gene-disease association is also supported by animal models, expression studies, in vitro functional assays, and rescue from cell culture models. (PMIDs: 8943028, 17881463, 20221250, 1378753, 1977575, 16368682, 14603255, 30998089). In particular, *PAX2* knockout mice caused papillorenal syndrome (PMIDs: 8943028, 17881463, 20221250) and PAX2 expression was demonstrated in normal human kidney and mouse CNS during nephrogenesis and neurogenesis respectively (PMIDs: 1378753, 1977575). Furthermore, in-vitro functional assays demonstrated PAX2 interaction with WNT4 (PMID: 16368682), which is critical for nephrogenesis, and WT1 (PMID: 14603255), which activates podocyte proteins nephrin and podocalyxin. Lastly, *PAX2* missense mutation corrected by CRISPR-Cas9 rescued podocyte mobility in a cell culture model (PMID: 30998089). In summary, *PAX2* is definitively associated with autosomal dominant nephropathy, with or without extra-renal features - *PAX2*. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic; Ophthalmologic; Renal
Intervention: Renal
Rationale: The disorders may be recognizable in some individuals, but individuals are at risk of renal findings such as unrecognized vesicoureteral reflux, which can cause renal damage, and early diagnosis to allow management may be beneficial
Comments: It has been suggested that variants may result in isolated renal hypoplasia without other manifestations, though on examination, many individuals have been found to have opthalmalogic anomalies
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PAX2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000278.5. 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 | 10 | 84 | 94 | |||
| missense | 7 | 40 | 221 | 18 | 286 | |
| nonsense | 19 | 10 | 29 | |||
| start loss | 2 | 2 | ||||
| frameshift | 32 | 28 | 5 | 65 | ||
| splice donor/acceptor (+/-2bp) | 9 | 11 | 2 | 22 | ||
| Total | 67 | 89 | 240 | 102 | 0 | 498 |
Highest pathogenic variant AF is 0.0000065116883
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000269.3 | 10 | MANE Select | |
| Ensembl | ENSP00000347385.3 | 10 | MANE Select | |
| RefSeq | NP_001291498.1 | 11 | Standard | |
| RefSeq | NP_001361232.1 | 3 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| pax2a | Danio rerio | Structure: midbrain hindbrain boundary neural keel Quality: physical object quality abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Primary Focal Segmental Glomerulosclerosis FSGS
- ID signaling pathway
- Wnt
Biological Process
- urogenital system development
- branching involved in ureteric bud morphogenesis
- cell fate determination
- mesonephros development
- neural tube closure
Molecular Function
- DNA-binding transcription factor activity, RNA polymerase II-specific
- proximal promoter sequence-specific DNA binding
- DNA binding
- protein binding
- transcription factor binding
Cellular Component
- nucleus
- nucleolus
- lysosome
- Golgi apparatus
- microtubule organizing center
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000428433
- Coding exons
- 11
- Length
- 94339
- Individuals with no LoFs
- 125733
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 14
- Defined
- 125747
- p
- 0.0000557
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.49 | 178 | 243 | 0.731 | 0.0000132 | 2669 |
| Missense (PolyPhen) | 53 | 100.47 | 0.52751 | 1081 | ||
| Synonymous | -1.09 | 113 | 99.1 | 1.14 | 0.00000550 | 877 |
| Loss of Function | 3.45 | 4 | 21.1 | 0.190 | 0.00000106 | 234 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000087 | 0.000087 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00045 | 0.00044 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000027 | 0.000026 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Transcription factor that may have a role in kidney cell differentiation (PubMed:24676634). Has a critical role in the development of the urogenital tract, the eyes, and the CNS. {ECO:0000269|PubMed:24676634}.;
- Disease
- DISEASE: Papillorenal syndrome (PAPRS) [MIM:120330]: An autosomal dominant disorder characterized by both ocular and renal anomalies, but may also include vesicoureteral reflux, high frequency hearing loss, central nervous system anomalies, and/or genital anomalies. Eye anomalies in this disorder consist of a wide and sometimes excavated dysplastic optic disk with the emergence of the retinal vessels from the periphery of the disk, designated optic nerve coloboma or 'morning glory' anomaly. Associated findings may include a small corneal diameter, retinal coloboma, scleral staphyloma, optic nerve cyst, microphthalmia, and pigmentary macular dysplasia. The kidneys are small and abnormally formed (renal hypodysplasia), and have fewer than the normal number of glomeruli, which are enlarged (oligomeganephronia). These ocular and renal anomalies result in decreased visual acuity and retinal detachment, as well as hypertension, proteinuria, and renal insufficiency that frequently progresses to end-stage renal disease. {ECO:0000269|PubMed:11168927, ECO:0000269|PubMed:15652857, ECO:0000269|PubMed:19954729, ECO:0000269|PubMed:22213154, ECO:0000269|PubMed:24676634, ECO:0000269|PubMed:9760197}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Focal segmental glomerulosclerosis 7 (FSGS7) [MIM:616002]: A renal pathology defined by the presence of segmental sclerosis in glomeruli and resulting in proteinuria, reduced glomerular filtration rate and progressive decline in renal function. Renal insufficiency often progresses to end-stage renal disease, a highly morbid state requiring either dialysis therapy or kidney transplantation. {ECO:0000269|PubMed:24676634}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.553
Intolerance Scores
- LoFtool
- 0.0842
- RVIS EVS
- -0.34
- RVIS percentile EVS
- 30.37
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.961
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |