PITX3

protein-coding

paired like homeodomain 3, 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. Members of this family act as transcription factors. This protein is involved in lens formation during eye development. Mutations of this gene have been associated with anterior segment mesenchymal dysgenesis and congenital cataracts. [provided by RefSeq, Jul 2008]

Previous symbols:

ASMD

MANE transcript

NM_005029.4

Inheritance

ClinVar variants

P:9U:62B:22

Top phenotype

Cataract 11, multiple types; Cataract 11, syndromic; Anterior segment dysgenesis 1

gnomAD constraint

pLI —, LoF o/e 0.1

Max pathogenic AF

—

Genomic locus

chr10:102,230,189-102,241,512

External References & Databases

Ensembl (ENSG00000107859)

Transcript & Mutation Effects

hg38 • Region Span ~11.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

anterior segment dysgenesis 1MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0007138

Submitter: Ambry Genetics

cataract-glaucoma syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015567

Submitter: Orphanet

anterior segment dysgenesis 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007138

Submitter: Labcorp Genetics (formerly Invitae)

early-onset posterior polar cataractSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0020378

Submitter: Orphanet

disorder of visual systemSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0024458

Submitter: PanelApp Australia

cataract 11 multiple typesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012527

Submitter: Labcorp Genetics (formerly Invitae)

anterior segment dysgenesis 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007138

Submitter: G2P

Clinical Genomic Database (CGD)

Cataract 11, multiple types; Cataract 11, syndromic; Anterior segment dysgenesis 1AD

Manifestation: Ophthalmologic

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

Refs: 6801987; 9620774; 10361984; 15286169; 16565358; 17888164; 18989383; 21633712; 22223473

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PITX3 variants in ClinVar

10 Conditions Cataloged

not providedTotal: 52

Inborn genetic diseasesTotal: 38

PITX3-related disorderTotal: 15

Cataract 11 multiple typesTotal: 6

not specifiedTotal: 4

Anterior segment dysgenesis 1Total: 3

Cataract 11, posterior polarTotal: 2

Cataract 11, posterior polar, with microphthalmia and neurodevelopmental abnormalitiesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005029.4. 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			1 clinvar	21 clinvar		22
missense		1 clinvar	58 clinvar	1 clinvar		60
nonsense		3 clinvar	1 clinvar			4
start loss						0
frameshift	3 clinvar	2 clinvar	2 clinvar			7
splice donor/acceptor (+/-2bp)						0
Total	3	6	62	22	0	93

Highest pathogenic variant AF is 0.00003972484

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 4 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005029.4	RefSeq	NP_005020.1	3	MANE Select
ENST00000370002.8	Ensembl	ENSP00000359019.3	3	MANE Select
ENST00001138199.1	Ensembl	ENSP00000809647.1	3	Standard
XM_047425352.1	RefSeq	XP_047281308.1	3	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
pitx3	Danio rerio	Structure: mandibular arch skeleton Quality: morphology abnormal

Gene / Model

Organism

Observed Phenotype

pitx3

Danio rerio

Structure: mandibular arch skeleton

Quality: morphology

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Dopaminergic Neurogenesis

Biological Process

lens development in camera-type eye
lens morphogenesis in camera-type eye
regulation of transcription, DNA-templated
aging
locomotory behavior

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
RNA polymerase II transcription factor binding
sequence-specific DNA binding

Cellular Component

nucleus
neuronal cell body

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000370002
Coding exons: 3
Length: 11289
Individuals with no LoFs: 110771
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 110772
p: 0.00000451

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.50	115	170	0.677	0.00000791	1874
Missense (PolyPhen)		14	38.755	0.36124		408
Synonymous	0.542	75	81.2	0.923	0.00000395	666
Loss of Function	2.62	1	9.90	0.101	4.24e-7	108

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000032	0.000032	rare
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: dbNSFP

Function: FUNCTION: Transcriptional regulator which is important for the differentiation and maintenance of meso-diencephalic dopaminergic (mdDA) neurons during development. In addition to its importance during development, it also has roles in the long-term survival and maintenance of the mdDA neurons. Activates NR4A2/NURR1- mediated transcription of genes such as SLC6A3, SLC18A2, TH and DRD2 which are essential for development of mdDA neurons. Acts by decreasing the interaction of NR4A2/NURR1 with the corepressor NCOR2/SMRT which acts through histone deacetylases (HDACs) to keep promoters of NR4A2/NURR1 target genes in a repressed deacetylated state. Essential for the normal lens development and differentiation. Plays a critical role in the maintenance of mitotic activity of lens epithelial cells, fiber cell differentiation and in the control of the temporal and spatial activation of fiber cell-specific crystallins. Positively regulates FOXE3 expression and negatively regulates PROX1 in the anterior lens epithelium, preventing activation of CDKN1B/P27Kip1 and CDKN1C/P57Kip2 and thus maintains lens epithelial cells in cell cycle (By similarity). {ECO:0000250}.;
Disease: DISEASE: Cataract 11, multiple types (CTRCT11) [MIM:610623]: An opacification of the crystalline lens of the eye that frequently results in visual impairment or blindness. Opacities vary in morphology, are often confined to a portion of the lens, and may be static or progressive. CTRCT11 includes posterior polar cataract, among others. Posterior polar cataract is a subcapsular opacity, usually disk-shaped, located at the back of the lens. Some CTRCT11 patients can present a severe phenotype including microphthalmia and neurological dysfunction. {ECO:0000269|PubMed:15286169, ECO:0000269|PubMed:9620774}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.193

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.647

Gene Damage Prediction

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