GeneBe

PHOX2A

protein-coding

paired like homeobox 2A, the group of PRD class homeoboxes and pseudogenes

Gene summary

The protein encoded by this gene contains a paired-like homeodomain most similar to that of the Drosophila aristaless gene product. The encoded protein plays a central role in development of the autonomic nervous system. It regulates the expression of tyrosine hydroxylase and dopamine beta-hydroxylase, two catecholaminergic biosynthetic enzymes essential for the differentiation and maintenance of the noradrenergic neurotransmitter phenotype. The encoded protein has also been shown to regulate transcription of the alpha3 nicotinic acetylcholine receptor gene. Mutations in this gene have been associated with autosomal recessive congenital fibrosis of the extraocular muscles. [provided by RefSeq, Jul 2008]

Previous symbols:
  • ARIX
  • FEOM2

MANE transcript

NM_005169.4

Inheritance

AD, AR

ClinVar variants

P:2U:32B:6

Top phenotype

Fibrosis of extraocular muscles, congenital, 2

gnomAD constraint

pLI —, LoF o/e 0.17

Max pathogenic AF

—

Genomic locus

chr11:72,239,077-72,245,664

External References & Databases

Ensembl (ENSG00000165462)NCBI Gene (401)OMIM (602753)HGNC:691GenCCUniProt (O14813)AlphaFoldClinVar (PHOX2A)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~6.6 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital fibrosis of extraocular musclesSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007614

Submitter: Orphanet

fibrosis of extraocular muscles, congenital, 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011181

Submitter: PanelApp Australia

fibrosis of extraocular muscles, congenital, 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011181

Submitter: G2P

fibrosis of extraocular muscles, congenital, 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011181

Submitter: Labcorp Genetics (formerly Invitae)

fibrosis of extraocular muscles, congenital, 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011181

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Fibrosis of extraocular muscles, congenital, 2AR

Manifestation: Musculoskeletal

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: 11600883Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PHOX2A variants in ClinVar

5 Conditions Cataloged
Inborn genetic diseasesTotal: 27
PHOX2A-related disorderTotal: 7
not providedTotal: 5
not specifiedTotal: 3
Fibrosis of extraocular muscles, congenital, 2Total: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005169.4. 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.

EffectPLPVUSLBBSum
synonymous
6
clinvar
 6
missense
32
clinvar
 32
nonsense
0
start loss
0
frameshift
0
splice donor/acceptor (+/-2bp)
2
clinvar
 2
Total20326040

Highest pathogenic variant AF is 0.0000018273084

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 7 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_005169.4RefSeqNP_005160.23MANE Select
ENST00000298231.5EnsemblENSP00000298231.53MANE Select
NM_001425096.1RefSeqNP_001412025.13Standard
NM_001425097.1RefSeqNP_001412026.13Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
phox2aDanio rerio

Structure: pharyngeal arch

Quality: has fewer parts of type

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways

Biological Process

  • noradrenergic neuron differentiation
  • nervous system development
  • somatic motor neuron differentiation
  • oculomotor nerve formation
  • trochlear nerve formation

Molecular Function

  • RNA polymerase II regulatory region sequence-specific DNA binding
  • DNA-binding transcription factor activity, RNA polymerase II-specific
  • DNA-binding transcription factor activity

Cellular Component

  • nuclear chromatin
  • nucleus

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000298231
Coding exons
3
Length
6588
Individuals with no LoFs
125589
Homozygous LoFs
0
Heterozygous LoFs
2
Defined
125591
p
0.00000796
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.60631100.5710.000005851761
Missense (PolyPhen)1121.6430.50825217
Synonymous2.292949.50.5860.00000267625
Loss of Function1.8815.960.1682.55e-794

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000180.000018rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: May be involved in regulating the specificity of expression of the catecholamine biosynthetic genes. Acts as a transcription activator/factor. Could maintain the noradrenergic phenotype.;
Disease
DISEASE: Fibrosis of extraocular muscles, congenital, 2 (CFEOM2) [MIM:602078]: A congenital ocular motility disorder marked by restrictive ophthalmoplegia affecting extraocular muscles innervated by the oculomotor and/or trochlear nerves. It is clinically characterized by anchoring of the eyes in downward gaze, ptosis, and backward tilt of the head. Congenital fibrosis of extraocular muscles type 2 may result from the defective development of the oculomotor (nIII), trochlear (nIV) and abducens (nVI) cranial nerve nuclei. {ECO:0000269|PubMed:11600883}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.156

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.801

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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