PHOX2B Gene: Paired Mesoderm Homeobox 2B
Key regulator of autonomic nervous system development; mutations cause congenital central hypoventilation syndrome and neuroblastoma susceptibility.
Gene Information Card
| Symbol | PHOX2B |
|---|---|
| Full Name | paired mesoderm homeobox 2B |
| Gene Type | protein-coding |
| Chromosomal Location | 4p13 |
| NCBI Gene ID | 8929 ncbi.nlm.nih.gov/gene/8929 |
| Ensembl ID | ENSG00000109132 |
| UniProt ID | Q99453 |
| OMIM ID | 603851 |
| HGNC ID | 9143 |
| Aliases | NBPhox, PMX2B, CCHS, NBL, PHOX2B homeobox |
Description
The PHOX2B gene encodes a homeodomain transcription factor that is essential for the development of the autonomic nervous system, particularly the noradrenergic and cholinergic neurons. It regulates the expression of genes involved in neuronal differentiation and survival. Mutations in PHOX2B are primarily associated with congenital central hypoventilation syndrome (CCHS), a rare disorder characterized by abnormal respiratory control, and also predispose to neuroblastoma and other neural crest-derived tumors.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Congenital central hypoventilation syndrome (CCHS) | Heterozygous in-frame duplications or frameshift mutations in the polyalanine tract (20-33 alanines) or non-polyalanine mutations lead to loss-of-function or dominant-negative effects, impairing PHOX2B transcriptional activity and disrupting autonomic neuron development. | ClinVar, OMIM; Amiel et al., 2003; Weese-Mayer et al., 2003 |
| Neuroblastoma | Rare missense mutations (e.g., p.Arg141Leu) or copy number alterations in PHOX2B can act as gain-of-function or dominant-negative, promoting tumorigenesis in neural crest-derived cells. | COSMIC, ClinVar; Mosse et al., 2004; Trochet et al., 2004 |
| Haddad syndrome (CCHS with Hirschsprung disease) | PHOX2B mutations, especially polyalanine expansions, impair development of neural crest-derived enteric neurons, leading to aganglionosis of the colon. | OMIM; Amiel et al., 2003 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain | 0.0 | Not detected in adult brain (GTEx) but expressed during development |
| Lung | 0.0 | Not expressed in adult lung |
| Adrenal gland | 0.0 | Not expressed in adult adrenal; fetal expression critical |
| Small intestine | 0.0 | Not expressed in adult; enteric neurons during development |
| Testis | 0.0 | Not expressed in adult testis |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| SH-SY5Y (neuroblastoma) | 0.0 | Low expression; used as model for neuronal differentiation |
| IMR-32 (neuroblastoma) | 0.0 | Low expression; PHOX2B mutations may alter expression |
| SK-N-BE(2) (neuroblastoma) | 0.0 | Low expression; not a typical cell line for PHOX2B studies |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| Polyalanine repeat expansion (20-33 alanines) | In-frame duplication | ~90% of CCHS cases | Expanded polyalanine tract causes protein misfolding and aggregation, leading to loss-of-function or dominant-negative effects. |
| Non-polyalanine missense mutations (e.g., p.Arg141Leu) | Missense | Rare in CCHS; more common in neuroblastoma | Altered DNA binding or transactivation, leading to loss-of-function or gain-of-function in tumor context. |
| Frameshift mutations (e.g., c.618_619insG) | Frameshift | Rare | Premature truncation, loss of function. |
| Copy number loss (heterozygous deletion) | Copy number variant | Rare | Haploinsufficiency leading to CCHS phenotype. |
Mutation functional classification
Loss of Function (LOF)
Most PHOX2B mutations, especially polyalanine expansions and frameshifts, result in loss of transcriptional activity, impairing neuronal differentiation.
Gain of Function (GOF)
Some missense mutations in neuroblastoma may confer oncogenic gain-of-function, promoting cell proliferation.
Dominant Negative (DN)
Polyalanine expansions can exert dominant-negative effects by interfering with wild-type PHOX2B function in heterozygous state.
View complete mutation data：
Gene Ontology (GO)
| • DNA-binding transcription factor activity | • RNA polymerase II cis-regulatory region sequence-specific DNA binding |
| • sequence-specific double-stranded DNA binding | • protein homodimerization activity |
| • regulation of transcription by RNA polymerase II | • nervous system development |
| • neural crest cell migration | • sympathetic nervous system development |
| • enteric nervous system development | • respiratory system process |
Pathways
• Development of the autonomic nervous system
• Neural crest differentiation
• Noradrenergic neuron differentiation
• Regulation of tyrosine hydroxylase expression
• RET signaling pathway (via PHOX2B regulation of RET)
Protein Summary
PHOX2B is a 314-amino acid homeodomain transcription factor with two polyalanine tracts. It contains a homeodomain that binds DNA and a C-terminal transactivation domain. It forms homodimers and interacts with other transcription factors like PHOX2A and E47. It is critical for the differentiation of noradrenergic neurons and the development of the autonomic nervous system. Mutations, particularly polyalanine expansions, lead to protein aggregation and loss of function, causing CCHS.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| PHOX2B Knockout HEK293 Cell Line | EDJ-KQ6400 | Human | 8929 | Details Get a Quote |
| PHOX2B Knockout HeLa Cell Line | EDJ-KQ55039 | Human | 8929 | Details Get a Quote |
| PHOX2B Knockout A-549 Cell Line | EDJ-KQ63523 | Human | 8929 | Details Get a Quote |
| PHOX2B Knockout HCT 116 Cell Line | EDJ-KQ71990 | Human | 8929 | Details Get a Quote |
