PAX4
protein-codingpaired box 4, the group of Paired boxes|PRD class homeoboxes and pseudogenes
Gene summary
This gene is a member of the paired box (PAX) family of transcription factors. Members of this gene family typically contain a paired box domain, an octapeptide, and a paired-type homeodomain. These genes play critical roles during fetal development and cancer growth. The paired box 4 gene is involved in pancreatic islet development and mouse studies have demonstrated a role for this gene in differentiation of insulin-producing beta cells. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~7.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0018911
Submitter: Orphanet
Inheritance Pattern: Unknown
Disease ID:MONDO:0012818
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0015967
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0015967
Submitter: ClinGen
*PAX4* was first reported in relation to autosomal dominant monogenic diabetes in in 2007 (Plengvidhya et al., 2007). At least 5 unique variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case-Level and Experimental data: 4.2 points. Variants in this gene have been reported in at least 5 probands in 4 publications (PMIDs: 25041077, 21263211, 28993341, 17426099). An in vitro functional assay provided evidence that one variant slightly reduces repression of insulin promoter activity (PMID 17426099). Laver et al (PMID: 3510838) reported a lack of enrichment of ultra-rare (MAF<6x10-6) protein-truncating and missense variants in *BLK*, *PAX4*, and *KLF11* in a large cohort of cases with suspected MODY (n=1227) compared to population cohort (UK Biobank =185,898), gnomADv2 and gnomADv3. They also showed a similar lack of enrichment of protein-truncating variants of any frequency in *BLK*, *PAX4*, and *KLF11* in the MODY cohort. In summary, there is limited evidence to support, and there appears to be strong evidence to contradict the *PAX4*-monogenic diabetes relationship that warrants refuting the association (originally asserted as maturity-onset diabetes of the young 9, MODY9, MIM: 612225). *PAX4* variants may play a role in susceptibility to polygenic type 2 diabetes (MIM: 125853) and have also been described in relation to susceptibility to an atypical presentation of non-autoimmune diabetes sometimes referred to as “ketosis-prone diabetes” (KPD, MIM: 612227), neither of which will be curated at this time since the contribution would be in the form of common variants with a small effect and moreover, evidence is limited.
Inheritance Pattern: Unknown
Disease ID:MONDO:0007455
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Endocrine
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PAX4 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001366110.1. 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 | 20 | 23 | |||
| missense | 88 | 16 | 1 | 105 | ||
| nonsense | 3 | 3 | ||||
| start loss | 0 | |||||
| frameshift | 4 | 4 | ||||
| splice donor/acceptor (+/-2bp) | 4 | 4 | ||||
| Total | 0 | 0 | 102 | 36 | 1 | 139 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001353039.1 | 10 | MANE Select | |
| Ensembl | ENSP00000491782.1 | 10 | MANE Select | |
| RefSeq | NP_001353040.1 | 10 | Standard | |
| Ensembl | ENSP00000339906.2 | 9 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| pax4 | Danio rerio | Structure: pancreatic A cell Quality: increased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Maturity onset diabetes of the young - Homo sapiens (human)
Biological Process
- negative regulation of transcription by RNA polymerase II
- circadian rhythm
- animal organ morphogenesis
- cell differentiation
- endocrine pancreas development
Molecular Function
- RNA polymerase II distal enhancer sequence-specific DNA binding
- DNA-binding transcription factor activity, RNA polymerase II-specific
- DNA-binding transcription repressor activity, RNA polymerase II-specific
- DNA binding
Cellular Component
- nucleoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000341640
- Coding exons
- 9
- Length
- 5637
- Individuals with no LoFs
- 125735
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 13
- Defined
- 125748
- p
- 0.0000517
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.560 | 211 | 189 | 1.11 | 0.0000120 | 2128 |
| Missense (PolyPhen) | 94 | 81.251 | 1.1569 | 858 | ||
| Synonymous | -0.651 | 80 | 72.9 | 1.10 | 0.00000362 | 764 |
| Loss of Function | 1.88 | 8 | 16.1 | 0.495 | 8.44e-7 | 173 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00011 | 0.00011 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Plays an important role in the differentiation and development of pancreatic islet beta cells. Transcriptional repressor that binds to a common element in the glucagon, insulin and somatostatin promoters. Competes with PAX6 for this same promoter binding site. Isoform 2 appears to be a dominant negative form antagonizing PAX4 transcriptional activity.;
- Disease
- DISEASE: Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]: A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:11723072}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Diabetes mellitus, insulin-dependent (IDDM) [MIM:222100]: A multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical features are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:15834548}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Diabetes mellitus, ketosis-prone (KPD) [MIM:612227]: An atypical form of diabetes mellitus characterized by an acute initial presentation with severe hyperglycemia and ketosis, as seen in classic type 1 diabetes, but after initiation of insulin therapy, prolonged remission is often possible with cessation of insulin therapy and maintenance of appropriate metabolic control. Metabolic studies show a markedly blunted insulin secretory response to glucose, partially reversible with the improvement of blood glucose control. Variable levels of insulin resistance are observed, especially in obese patients. Pancreatic beta-cell autoimmunity is a rare finding. {ECO:0000269|PubMed:15509590}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Maturity-onset diabetes of the young 9 (MODY9) [MIM:612225]: A form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease. {ECO:0000269|PubMed:17426099}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.215
Intolerance Scores
- LoFtool
- 0.174
- RVIS EVS
- 0.49
- RVIS percentile EVS
- 79.46
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.421
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |