PITX2
protein-codingpaired like homeodomain 2, the group of PRD class homeoboxes and pseudogenes
Gene summary
This gene encodes a member of the RIEG/PITX homeobox family, which is in the bicoid class of homeodomain proteins. The encoded protein acts as a transcription factor and regulates procollagen lysyl hydroxylase gene expression. This protein plays a role in the terminal differentiation of somatotroph and lactotroph cell phenotypes, is involved in the development of the eye, tooth and abdominal organs, and acts as a transcriptional regulator involved in basal and hormone-regulated activity of prolactin. Mutations in this gene are associated with Axenfeld-Rieger syndrome, iridogoniodysgenesis syndrome, and sporadic cases of Peters anomaly. A similar protein in other vertebrates is involved in the determination of left-right asymmetry during development. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jul 2008]
- IRID2
- IHG2
- RIEG
- RIEG1
- RGS
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~24.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0007662
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0008386
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0019187
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008386
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0019628
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0020368
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008387
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0018054
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008386
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0008387
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0011414
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0019172
Submitter: Genomics England PanelApp
Inheritance Pattern: Unknown
Disease ID:MONDO:0008387
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0024458
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0007662
Submitter: ClinGen
Variation in the *PITX2* gene was first reported in relation to Axenfeld-Rieger syndrome in 1996 (Semina et al., PMID: 8944018]). Affected patients exhibit ocular features that are localized to the anterior segment, and frequently include iris hypoplasia, corectopia, polycoria, posterior embryotoxon, and predisposition to the development of glaucoma. A subset of patients exhibits additional extraocular features, including redundant periumbilical skin or umbilical hernia, and dental abnormalities such as hypodontia and/or microdontia. Patients with ocular presentation only may be diagnosed with anterior segment dysgenesis, which was first reported in relation to *PITX2* in 1998 (PMID: 9437321, PMID: 9618168). Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the molecular mechanism (monoallelic loss of function) and mode of inheritance (autosomal dominant) were found to be consistent among patients with Axenfeld-Rieger syndrome 1 and anterior segment dysgenesis 4, while the phenotypic variability between them appeared to represent a spectrum of disease rather than separate disease entities. Therefore, cases caused by inherited *PITX2* variants have been lumped into a single disease entity, referred to as *PITX2*-related anterior segment dysgenesis syndrome. This curation has scored sixteen suspected disease-causing variants (one nonsense, six frameshift, two predicted to disrupt splicing, five missense affecting the homeobox domain of the encoded protein, and two additional missense variants). These variants have been collectively reported in sixteen probands in five publications (PMID: 8944018, PMID: 9437321, PMID: 12381896, PMID: 28513611, PMID: 35882526). Three of the probands were associated with large families in which the variant co-segregated with the affected status of family members (PMID: 8944018, PMID: 9437321). More case-level evidence is available in the literature (PMID: 19513095), but its inclusion in this curation was not necessary to reach the maximum score for genetic evidence (12 points). The mechanism of pathogenicity appears to be monoallelic loss of function, characterized in some cases by truncation of the majority of the protein product and in other cases by missense variants within the homeobox domain that cause defects in transactivation (PMID: 19218601). This gene-disease association is supported by biochemical evidence that PITX2 functions as a transcription factor to coordinate normal tissue development (PMID: 23975681). *PITX2* is highly expressed in ocular tissues, particularly the cornea, retinal pigment epithelium and trabecular meshwork (PMID: 30239781). PITX2 physically interacts with and colocalizes with FOXC1, another transcription factor associated with Axenfeld-Rieger syndrome through an autosomal dominant mode of inheritance (PMID: 16449236). Phenotypes of affected human patients are recapitulated by various model organisms with *PITX2* loss-of-function, including defective anterior segment development and dental abnormalities in mice that are consistent with the proposed role of PITX2 in the genesis of these tissues (PMID: 10498698, PMID: 16203745). In summary, *PITX2* has a Definitive association with *PITX2*-related anterior segment dysgenesis syndrome. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence. This classification was approved by the ClinGen Glaucoma and Neuro-Ophthalmology Gene Curation Expert Panel on July 17th, 2025 (SOP Version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0007662
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Dental; Ophthalmologic
Intervention: Ophthalmologic; Pharmacogenomic
Rationale: Individuals have a high risk of developing glaucoma, but treatment may not be effective in the majority of cases; Agents that may contribute to glaucoma should be avoided
Comments: Severe and difficult to treat glaucoma has been reported in many individuals with Anterior segment dysgenesis
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PITX2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000325.6. 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 | 23 | 1 | 27 | ||
| missense | 12 | 14 | 56 | 5 | 1 | 88 |
| nonsense | 13 | 4 | 1 | 18 | ||
| start loss | 0 | |||||
| frameshift | 24 | 12 | 36 | |||
| splice donor/acceptor (+/-2bp) | 5 | 1 | 6 | |||
| Total | 54 | 31 | 60 | 28 | 2 | 175 |
Highest pathogenic variant AF is 0.00000615654
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000316.2 | 3 | MANE Select | |
| Ensembl | ENSP00000495061.1 | 3 | MANE Select | |
| RefSeq | NP_001191326.1 | 4 | Standard | |
| RefSeq | NP_001191327.1 | 4 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| pitx2 | Danio rerio | Structure: endodermal cell Quality: movement quality abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- TGF-beta signaling pathway - Homo sapiens (human)
- WNT-Ncore
- Heart Development
- Mesodermal Commitment Pathway
- BMP Signaling Pathway in Eyelid Development
Biological Process
- cardiac neural crest cell migration involved in outflow tract morphogenesis
- regulation of transcription, DNA-templated
- regulation of transcription by RNA polymerase II
- determination of left/right symmetry
- anatomical structure morphogenesis
Molecular Function
- transcription regulatory region sequence-specific DNA binding
- RNA polymerase II proximal promoter sequence-specific DNA binding
- DNA-binding transcription factor activity, RNA polymerase II-specific
- RNA polymerase II transcription factor binding
- RNA polymerase II activating transcription factor binding
Cellular Component
- nucleus
- nucleoplasm
- transcription factor complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000306732
- Coding exons
- 3
- Length
- 24701
- Individuals with no LoFs
- 0
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 0
- Defined
- 0
- p
- 0.00
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.55 | 124 | 183 | 0.678 | 0.00000839 | 2102 |
| Missense (PolyPhen) | 45 | 78.357 | 0.57429 | 913 | ||
| Synonymous | -0.668 | 87 | 79.4 | 1.10 | 0.00000386 | 653 |
| Loss of Function | 3.14 | 0 | 11.5 | 0.00 | 5.01e-7 | 123 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Controls cell proliferation in a tissue-specific manner and is involved in morphogenesis. During embryonic development, exerts a role in the expansion of muscle progenitors. May play a role in the proper localization of asymmetric organs such as the heart and stomach. Isoform PTX2C is involved in left-right asymmetry the developing embryo (By similarity). {ECO:0000250}.;
- Disease
- DISEASE: Axenfeld-Rieger syndrome 1 (RIEG1) [MIM:180500]: An autosomal dominant disorder of morphogenesis that results in abnormal development of the anterior segment of the eye, and results in blindness from glaucoma in approximately 50% of affected individuals. Additional features include aniridia, maxillary hypoplasia, hypodontia, anal stenosis, redundant periumbilical skin. {ECO:0000269|PubMed:10937553, ECO:0000269|PubMed:11487566, ECO:0000269|PubMed:12381896, ECO:0000269|PubMed:16936096, ECO:0000269|PubMed:8944018}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Anterior segment dysgenesis 4 (ASGD4) [MIM:137600]: 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. ASGD4 is an autosomal dominant disease. {ECO:0000269|PubMed:10051017, ECO:0000269|PubMed:20881294, ECO:0000269|PubMed:9437321, ECO:0000269|PubMed:9618168}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Ring dermoid of cornea (RDC) [MIM:180550]: An ocular disorder characterized by bilateral annular limbal dermoids (growths with a skin-like structure) with corneal and conjunctival extension. {ECO:0000269|PubMed:15591271, ECO:0000269|PubMed:22224469}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.635
Intolerance Scores
- LoFtool
- 0.0743
- 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
- 0.997
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |