PHOX2B

Summary

PHOX2B (paired like homeobox 2B, HGNC:9143) is a protein-coding gene on chromosome 4p13, encoding Paired mesoderm homeobox protein 2B (Q99453). Involved in the development of several major noradrenergic neuron populations, including the locus coeruleus. It is haploinsufficient (ClinGen: sufficient evidence).

The DNA-associated protein encoded by this gene is a member of the paired family of homeobox proteins localized to the nucleus. The protein functions as a transcription factor involved in the development of several major noradrenergic neuron populations and the determination of neurotransmitter phenotype. The gene product is linked to enhancement of second messenger-mediated activation of the dopamine beta-hydroylase, c-fos promoters and several enhancers, including cyclic amp-response element and serum-response element. Expansion of a 20 amino acid polyalanine tract in this protein by 5-13 aa has been associated with congenital central hypoventilation syndrome.

Source: NCBI Gene 8929 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Haddad syndrome (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 1,085 total — 36 pathogenic, 13 likely-pathogenic
• Phenotypes (HPO): 78
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Transcription factor: yes — 18 downstream targets (CollecTRI)
• MANE Select transcript: NM_003924

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9143
Approved symbol	PHOX2B
Name	paired like homeobox 2B
Location	4p13
Locus type	gene with protein product
Status	Approved
Aliases	NBPhox
Ensembl gene	ENSG00000109132
Ensembl biotype	protein_coding
OMIM	603851
Entrez	8929

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000226382, ENST00000510424

RefSeq mRNA: 1 — MANE Select: NM_003924 NM_003924

CCDS: CCDS3463

Canonical transcript exons

ENST00000226382 — 3 exons

Exon	Start	End
ENSE00001014991	41748370	41748725
ENSE00001014992	41744082	41746322
ENSE00003743222	41747349	41747536

Expression profiles

Bgee: expression breadth broad, 53 present calls, max score 66.03.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.8886 / max 437.1155, expressed in 58 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
51947	0.5766	41
51949	0.1228	16
51952	0.0896	14
51948	0.0431	9
51951	0.0276	8
51950	0.0265	7
51943	0.0023	1

Top tissues by expression

264 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
muscle layer of sigmoid colon	UBERON:0035805	66.03	gold quality
buccal mucosa cell	CL:0002336	65.10	silver quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	64.69	silver quality
inferior olivary complex	UBERON:0002127	63.65	silver quality
sigmoid colon	UBERON:0001159	61.27	gold quality
colonic epithelium	UBERON:0000397	61.09	gold quality
cranial nerve II	UBERON:0000941	59.48	silver quality
endometrium epithelium	UBERON:0004811	59.13	gold quality
pancreatic ductal cell	CL:0002079	58.72	silver quality
ileal mucosa	UBERON:0000331	58.70	silver quality
rectum	UBERON:0001052	57.77	gold quality
tendon of biceps brachii	UBERON:0008188	57.15	gold quality
tibialis anterior	UBERON:0001385	57.06	silver quality
colon	UBERON:0001155	57.02	gold quality
large intestine	UBERON:0000059	56.50	gold quality
adrenal tissue	UBERON:0018303	55.55	gold quality
intestine	UBERON:0000160	55.31	gold quality
transverse colon	UBERON:0001157	54.94	gold quality
vermiform appendix	UBERON:0001154	54.77	gold quality
caecum	UBERON:0001153	54.56	gold quality
deltoid	UBERON:0001476	53.20	gold quality
epithelial cell of pancreas	CL:0000083	50.98	gold quality
quadriceps femoris	UBERON:0001377	50.98	gold quality
frontal pole	UBERON:0002795	50.41	gold quality
small intestine	UBERON:0002108	50.32	gold quality
middle frontal gyrus	UBERON:0002702	50.30	gold quality
paraflocculus	UBERON:0005351	50.18	gold quality
Brodmann (1909) area 10	UBERON:0013541	50.18	gold quality
thymus	UBERON:0002370	50.15	silver quality
right adrenal gland	UBERON:0001233	49.65	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-HCAD-56	yes	619.88
E-HCAD-10	yes	4.76
E-ANND-3	no	1.80

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

18 targets.

Target	Regulation
ALK	Activation
CEL
DBH	Activation
FOS	Activation
GAD1
HAND1
HAND2
HPCAL1
ISL1	Activation
MSX1	Repression
OLIG2	Repression
PAX6	Repression
PHOX2A	Unknown
PHOX2B	Activation
RET	Activation
SLC6A2	Activation
TH
TLX2	Activation

JASPAR motifs

Motif	Name	Family
MA0681.1	Phox2b	Paired-related HD factors
MA0681.2	PHOX2B	Paired-related HD factors
MA0681.3	PHOX2B	Paired-related HD factors

JASPAR matrix evidence (PMIDs): PMID:22323723

Upstream regulators (CollecTRI, top): HAND1, HAND2, HOXB2, PHOX2A, PHOX2B, SOX10, TLX2, TWIST1

miRNA regulators (miRDB)

84 targeting PHOX2B, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-7153-5P	99.94	68.89	1006
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-6794-5P	99.76	66.38	1048
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-494-3P	99.70	71.45	2795

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• PHOX2B has a role in the normal patterning of the autonomous ventilation system and, more generally, of the ANS in humans (PMID:12640453)
• A de novo t(4;8)(p13;p22) translocation in a girl with Hirschsprung’s disease contained a 4p12p13 deletion affecting the PMX2B gene. PMX2B haploinsuffciency might predispose to HSCR. (PMID:12919134)
• germline mutations of PHOX2B in both a familial case of neuroblastoma and a patient with the HSCR-NB association; PHOX2B, therefore, stands as the first gene for which germline mutations predispose to NB (PMID:15024693)
• PHOX2B gene in 23 cases of SIDS and did not find any mutations, except for three polymorphic nucleotidic substitutions; the mutation of PHOX2B is thus not likely associated with SIDS (PMID:15185974)
• Data report the molecular cloning and characterization of the promoter region of the human Phox2b gene. (PMID:15193420)
• report the first analysis of Phox2B in a series of 237 sporadic neuroblastomas and 22 cell lines (PMID:15516980)
• patients with congenital central hypoventilation syndrome who develop malignant tumors of the sympathetic nervous system harbor either a missense or a frameshift heterozygous mutation of the PHOX2B gene (PMID:15657873)
• PHOX2B may have a role in causing pediatric disorders with autonomic dysfunction [review] (PMID:15901893)
• the polymorphisms of the ARIX gene and PHOX2B gene may be genetic risk factors for the development of congenital superior oblique muscle palsy (PMID:16049556)
• PHOX2A, but not PHOX2B, seems to act directly on the c-RET promoter (PMID:16127999)
• A possible molecular explanation for the maintenance of PHOX2B expression in developing ganglia, in which it is initially controlled by other factors and is later self-regulated, is reported. (PMID:16144830)
• Molecular basis of impaired PHOX2B function due to missense, frameshift and alanine expansion mutations leading to autonomic dysfunction was determined. (PMID:16249188)
• These results demonstrate the direct interactions of the Phox2a and b and dHAND transcription factors within a noradrenergic cell type. (PMID:16280598)
• These results support the PHOX2B-TLX2 promoter interaction, suggesting a physiological role in the transcription-factor cascade underlying the differentiation of neuronal lineages of the Autonomic Nervous System during human embryogenesis. (PMID:16402914)
• PHOX2B analysis in non-syndromic neuroblastoma cases shows novel mutations and genotype-phenotype associations. (PMID:16691592)
• PHOX2B plays exclusive role in the pathogenesis of CCHS. (PMID:16763219)
• a polymorphism in paired like homeobox (PHOX) 2B gene may have a role in sudden infant death syndrome (PMID:16830328)
• adults have the mildest of the CCHS-related PHOX2B polyalanine expansion mutations, coding for only five extra alanines; three of the adults have affected offspring. (PMID:16873766)
• Congenital central hypoventilation syndrome associated nonpolyalanine repeat mutations in PHOX2B are mostly de novo, predominantly affect the 3’end of PHOX2B, and generally associated with a more severe phenotype. (PMID:16888290)
• study demonstrates that the interaction between RET and PHOX2B polymorphisms has a substantial impact on risk of Hirschsprung’s disease (PMID:17440194)
• PHOX2B, like PHOX2A, is involved in the cascade leading to transcription factor TLX2 transactivation and presumably is involved in intestinal neuronal differentiation. (PMID:17505528)
• PHOX2B polyalanine expansion mutation affects the development of the autonomic nervous system leading to autonomic dysfunction in congenital central hypoventilation syndrome. (PMID:17541758)
• PHOX2B alterations are a rare cause of hereditary neuroblastoma, but disruption of this neurodevelopmental pathway can interfere with transcription-dependent terminal differentiation. (PMID:17637745)
• No mutation was identified but LOH in about 10% of the cases and aberrant CpG dinucleotide methylation of the 500 bp PHOX2B promoter region in 4/31 tumours and cell lines (12.9%). Both germinal and somatic anomalies at the PHOX2B locus are found in NB. (PMID:17765533)
• PHOX2B genotype is related to the severity of cardiac autonomic dysregulation in congenital central hypoventilation syndrome. (PMID:18041756)
• 17 heterozygous PHOX2B gene mutations were fiybd in 25 patients with Late-onset central hypoventilation syndrome ;the most common mutation results in an expansion+5 alanines (PMID:18079495)
• Parental origin and somatic mosaicism of paired-like homeobox 2b mutations in Congenital Central Hypoventilation Syndrome (PMID:18157832)
• show that mice bearing a mutation in Phox2b that causes congenital central hypoventilation syndrome in humans breathe irregularly (PMID:18198276)
• This study suggests a potential role for Trim11 in the specification of NA phenotype by interaction with Phox2b. (PMID:18275850)
• Loss of PHOX2B and 17q gain are early events in neuroblastoma tumourigenesis. (PMID:18292934)
• a heterozygous 15-nucleotide deletion, PHOX2B 1124del15, resulting in loss of 5 alanine residues in the alanine repeat, was found in a daughter with muscle palsy and her father with normal traits, but was not found in her mother with muscle palsy (PMID:18323871)
• report a patient with a Congenital Central Hypoventilation Syndrome (CCHS) phenotype and homozygosity for a PHOX2B gene mutation leading to an alanine expansion shorter than the threshold hitherto observed in CCHS patients with a heterozygous mutation (PMID:18407552)
• the data support a model in which RET and PHOX2B contribute to the combined phenotype in congenital central hypoventilation syndrome combined with Hirschsprung disease (PMID:18438890)
• Congenital central hypoventilation syndrome associated with genetic variation in the PHOX2B gene. (PMID:18798833)
• PHOX2A and PHOX2B genes are highly co-expressed in human neuroblastoma. (PMID:18949361)
• sequencing the complete PHOX2b coding region in tumors from 69 patients with sporadic neuroblastomas revealed missense mutation, silent mutation and a new polymorphism (PMID:19011468)
• PHOX2B misfolding is not the only mechanism leading to dysfunction of the ventilatory autonomic system. (PMID:19058226)
• The human PHOX2B locus contained functional non-conserved regulatory sequences in addition to conserved PHOX2B functional elements. The distribution of regulatory elements is nonuniform. (PMID:19128492)
• Results demonstrated that aberrant interaction of PHOX2B mutants with CBP and/or an interfering effect of certain PHOX2B mutants may be the critical mechanism to impair synergistic activation, thereby contributing to the phenotypes of CCHS. (PMID:19191321)
• PHOX2B mutation is confirmed in congenital central hypoventilation syndrome. (PMID:19201717)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	phox2bb	ENSDARG00000091029
mus_musculus	Phox2b	ENSMUSG00000012520
rattus_norvegicus	Phox2b	ENSRNOG00000089491

Paralogs (50): ARX (ENSG00000004848), PAX6 (ENSG00000007372), PAX7 (ENSG00000009709), ALX4 (ENSG00000052850), GSC2 (ENSG00000063515), PITX1 (ENSG00000069011), PAX2 (ENSG00000075891), RHOXF1 (ENSG00000101883), CRX (ENSG00000105392), EVX1 (ENSG00000106038), PAX4 (ENSG00000106331), NOBOX (ENSG00000106410), PITX3 (ENSG00000107859), OTX1 (ENSG00000115507), PRRX1 (ENSG00000116132), VSX2 (ENSG00000119614), ESX1 (ENSG00000123576), PAX8 (ENSG00000125618), PAX1 (ENSG00000125813), RHOXF2 (ENSG00000131721), GSC (ENSG00000133937), RAX (ENSG00000134438), PAX3 (ENSG00000135903), ALX3 (ENSG00000156150), HESX1 (ENSG00000163666), PITX2 (ENSG00000164093), UNCX (ENSG00000164853), PHOX2A (ENSG00000165462), OTX2 (ENSG00000165588), DRGX (ENSG00000165606), PRRX2 (ENSG00000167157), SHOX2 (ENSG00000168779), OTP (ENSG00000171540), RAX2 (ENSG00000173976), EVX2 (ENSG00000174279), PROP1 (ENSG00000175325), ISX (ENSG00000175329), ALX1 (ENSG00000180318), MIXL1 (ENSG00000185155), SHOX (ENSG00000185960)

Protein

Protein identifiers

Paired mesoderm homeobox protein 2B — Q99453 (reviewed: Q99453)

Alternative names: Neuroblastoma Phox, PHOX2B homeodomain protein, Paired-like homeobox 2B

All UniProt accessions (1): Q99453

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the development of several major noradrenergic neuron populations, including the locus coeruleus. Transcription factor which could determine a neurotransmitter phenotype in vertebrates. Enhances second-messenger-mediated activation of the dopamine beta-hydrolase and c-fos promoters, and of several enhancers including cAMP-response element and serum-response element.

Subunit / interactions. Interacts with TRIM11.

Subcellular location. Nucleus.

Tissue specificity. Expressed in neuroblastoma, brain and adrenal gland.

Disease relevance. Central hypoventilation syndrome, congenital, 1 (CCHS1) [MIM:209880] An autosomal dominant form of congenital central hypoventilation syndrome, a rare disorder characterized by abnormal control of respiration in the absence of neuromuscular or lung disease, or an identifiable brain stem lesion. A deficiency in autonomic control of respiration results in inadequate or negligible ventilatory and arousal responses to hypercapnia and hypoxemia. The disease is caused by variants affecting the gene represented in this entry. Neuroblastoma 2 (NBLST2) [MIM:613013] A common neoplasm of early childhood arising from embryonic cells that form the primitive neural crest and give rise to the adrenal medulla and the sympathetic nervous system. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Similarity. Belongs to the paired homeobox family.

RefSeq proteins (1): NP_003915* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR017970	Homeobox_CS	Conserved_site
IPR050649	Paired_Homeobox_TFs	Family

Pfam: PF00046

UniProt features (20 total): sequence variant 8, compositionally biased region 4, helix 3, region of interest 2, chain 1, DNA-binding region 1, sequence conflict 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
7MJA	X-RAY DIFFRACTION	1.69
8EK5	X-RAY DIFFRACTION	2.11
8P7G	SOLUTION NMR
8PTL	SOLUTION NMR
8PUI	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99453-F1	61.94	0.21

Antibody-complex structures (SAbDab): 1 — 8EK5

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 477 (showing top): MORF_ITGA2, RNGTGGGC_UNKNOWN, FXR_IR1_Q6, GOBP_HINDBRAIN_DEVELOPMENT, YAATNRNNNYNATT_UNKNOWN, GOBP_RESPIRATORY_GASEOUS_EXCHANGE_BY_RESPIRATORY_SYSTEM, GOBP_NEGATIVE_REGULATION_OF_NEURON_DIFFERENTIATION, GOBP_MUSCLE_TISSUE_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GRUETZMANN_PANCREATIC_CANCER_DN, CMYB_01, GOBP_REGULATION_OF_RESPIRATORY_SYSTEM_PROCESS, GOBP_POSITIVE_REGULATION_OF_NEURON_DIFFERENTIATION, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_POSITIVE_REGULATION_OF_MITOTIC_CELL_CYCLE

GO Biological Process (40): neuron migration (GO:0001764), regulation of respiratory gaseous exchange by nervous system process (GO:0002087), noradrenergic neuron differentiation (GO:0003357), noradrenergic neuron development (GO:0003358), brainstem development (GO:0003360), regulation of transcription by RNA polymerase II (GO:0006357), glial cell differentiation (GO:0010001), regulation of gene expression (GO:0010468), positive regulation of G2/M transition of mitotic cell cycle (GO:0010971), response to activity (GO:0014823), cell differentiation in hindbrain (GO:0021533), medullary reticular formation development (GO:0021723), hindbrain tangential cell migration (GO:0021934), skeletal muscle cell differentiation (GO:0035914), type B pancreatic cell proliferation (GO:0044342), negative regulation of neuron differentiation (GO:0045665), positive regulation of neuron differentiation (GO:0045666), positive regulation of transcription by RNA polymerase II (GO:0045944), autonomic nervous system development (GO:0048483), enteric nervous system development (GO:0048484), sympathetic nervous system development (GO:0048485), parasympathetic nervous system development (GO:0048486), neuron development (GO:0048666), inner ear development (GO:0048839), efferent axon development in a lateral line nerve (GO:0048894), membrane depolarization (GO:0051899), respiratory system development (GO:0060541), retrotrapezoid nucleus neuron differentiation (GO:0061452), sympathetic ganglion development (GO:0061549), cellular response to carbon dioxide (GO:0071244), dopaminergic neuron differentiation (GO:0071542), cellular response to BMP stimulus (GO:0071773), motor neuron migration (GO:0097475), positive regulation of cold-induced thermogenesis (GO:0120162), neural crest cell migration involved in autonomic nervous system development (GO:1901166), negative regulation of type B pancreatic cell proliferation (GO:1904691), regulation of DNA-templated transcription (GO:0006355), cell population proliferation (GO:0008283), neuron differentiation (GO:0030182), cell development (GO:0048468)

GO Molecular Function (6): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677)

GO Cellular Component (3): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
neuron differentiation	3
cell differentiation	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
anatomical structure development	2
transcription by RNA polymerase II	2
regulation of neuron differentiation	2
regulation of transcription by RNA polymerase II	2
system development	2
cellular anatomical structure	2
cell migration	1
generation of neurons	1
respiratory gaseous exchange by respiratory system	1
regulation of respiratory system process	1
nervous system process	1
noradrenergic neuron differentiation	1
neuron development	1
regulation of DNA-templated transcription	1
gliogenesis	1
gene expression	1
regulation of macromolecule biosynthetic process	1
G2/M transition of mitotic cell cycle	1
regulation of G2/M transition of mitotic cell cycle	1
positive regulation of mitotic cell cycle phase transition	1
positive regulation of cell cycle G2/M phase transition	1
response to stimulus	1
hindbrain development	1
medulla oblongata development	1
cell migration in hindbrain	1
skeletal muscle tissue development	1
epithelial cell proliferation	1
negative regulation of cell differentiation	1
positive regulation of cell differentiation	1
positive regulation of DNA-templated transcription	1
nervous system development	1
autonomic nervous system development	1
transcription cis-regulatory region binding	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1

Protein interactions and networks

STRING

1208 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PHOX2B	ASCL1	P50553	892
PHOX2B	HAND2	P61296	823
PHOX2B	DBH	P09172	820
PHOX2B	EDN3	P14138	784
PHOX2B	RET	P07949	778
PHOX2B	ISL1	P20663	765
PHOX2B	TH	P07101	759
PHOX2B	GDNF	P39905	747
PHOX2B	GATA3	P23771	738
PHOX2B	EDNRB	P24530	730
PHOX2B	SOX10	P56693	720
PHOX2B	MYCN	P04198	685
PHOX2B	NEUROG2	Q9H2A3	654
PHOX2B	TBX2	Q13207	630
PHOX2B	CIBAR2	Q6ZTR7	625

IntAct

0 interactions, top by confidence:

BioGRID (7): CREBBP (Affinity Capture-Western), PHOX2B (Affinity Capture-Western), PHOX2B (Affinity Capture-MS), PHOX2B (Affinity Capture-MS), PHOX2B (Affinity Capture-MS), PHOX2B (Proximity Label-MS), PHOX2B (Affinity Capture-MS)

ESM2 similar proteins: A4L7N3, A6NJ46, O09113, O35160, O35690, O35762, O42115, O42567, O75364, O93385, P09027, P31249, P31314, P31316, P32443, P43120, P43241, P43345, P48031, P50222, P52951, P56673, P70314, P78337, P78426, P81062, P97474, Q04649, Q04742, Q06453, Q2NKI2, Q566X8, Q5XKR4, Q60554, Q6DGH9, Q8IVH2, Q8JI10, Q8K3Q3, Q8NFW5, Q91ZK4

Diamond homologs: A0A1W2PPK0, A0A1W2PPM1, A1A546, A1YEY5, A1YFI3, A1YG57, A1YGA2, A2T733, A2T777, A2T7P4, A6NFQ7, G5EC89, L8E946, O14813, O15499, O35690, O42250, O42356, O42357, O42477, O70137, O73917, O75360, O95076, O97670, P0DMV5, P26367, P26630, P29454, P41935, P47237, P47238, P53544, P53545, P53546, P54366, P55813, P55864, P56915, P56916

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
TRIM11	down-regulates	PHOX2B	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

1085 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	36
Likely pathogenic	13
Uncertain significance	595
Likely benign	367
Benign	21

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1029784	NM_003924.4(PHOX2B):c.292C>T (p.Gln98Ter)	Pathogenic
1032169	NM_003924.4(PHOX2B):c.945A>C (p.Ter315Cys)	Pathogenic
1072410	NM_003924.4(PHOX2B):c.691_698dup (p.Gly234fs)	Pathogenic
1323445	NM_003924.4(PHOX2B):c.750_779dup (p.Ala251_Ala260dup)	Pathogenic
1457266	NM_003924.4(PHOX2B):c.692del (p.Gly231fs)	Pathogenic
1736181	NM_003924.4(PHOX2B):c.391del (p.Leu131fs)	Pathogenic
1739403	NM_003924.4(PHOX2B):c.428A>G (p.Gln143Arg)	Pathogenic
1739416	NM_003924.4(PHOX2B):c.428dup (p.Val144fs)	Pathogenic
1742301	NM_003924.4(PHOX2B):c.466C>T (p.Gln156Ter)	Pathogenic
1747796	NM_003924.4(PHOX2B):c.547G>T (p.Glu183Ter)	Pathogenic
1749601	NM_003924.4(PHOX2B):c.577del (p.Asp193fs)	Pathogenic
1754025	NM_003924.4(PHOX2B):c.652_683del (p.Pro218fs)	Pathogenic
1756725	NM_003924.4(PHOX2B):c.702_714dup (p.Gly239fs)	Pathogenic
1758455	NM_003924.4(PHOX2B):c.735_767dup (p.Ala260_Gly261insAlaAlaAlaAlaAlaAlaAlaAlaAlaAlaAla)	Pathogenic
1760500	NM_003924.4(PHOX2B):c.776_777insGGCGGCCGCGGCAGCGGCGGC (p.Ala260_Gly261insAlaAlaAlaAlaAlaAlaAla)	Pathogenic
1763088	NM_003924.4(PHOX2B):c.836_843del (p.Pro279fs)	Pathogenic
1766546	NM_003924.4(PHOX2B):c.931_935del (p.Ser311fs)	Pathogenic
2500068	NM_003924.4(PHOX2B):c.778_779insGGCGGCGGCGGCAGCGGCAGCGGCGGCAGC (p.Ala260delinsGlyArgArgArgGlnArgGlnArgArgGlnPro)	Pathogenic
2625352	NM_003924.4(PHOX2B):c.747_773dup (p.Ala260_Gly261insAlaAlaAlaAlaAlaAlaAlaAlaAla)	Pathogenic
2633086	NM_003924.4(PHOX2B):c.684dup (p.Pro229fs)	Pathogenic
2846183	NM_003924.4(PHOX2B):c.479_480dup (p.Ala161fs)	Pathogenic
2851099	NM_003924.4(PHOX2B):c.195C>A (p.Cys65Ter)	Pathogenic
3223580	NM_003924.4(PHOX2B):c.196del (p.Ser66fs)	Pathogenic
3254839	NM_003924.4(PHOX2B):c.666_667del (p.Ala223fs)	Pathogenic
3347641	NM_003924.4(PHOX2B):c.390_398delinsTCTTCAG (p.Glu130fs)	Pathogenic
429242	NM_003924.4(PHOX2B):c.765_779dup (p.Ala256_Ala260dup)	Pathogenic
4813344	NM_003924.4(PHOX2B):c.651_760del (p.Pro218fs)	Pathogenic
521682	NM_003924.4(PHOX2B):c.945A>G (p.Ter315Trp)	Pathogenic
535775	NM_003924.4(PHOX2B):c.220C>T (p.Gln74Ter)	Pathogenic
6009	NM_003924.4(PHOX2B):c.618dup (p.Ser207fs)	Pathogenic

SpliceAI

418 predictions. Top by Δscore:

Variant	Effect	Δscore
4:41746329:C:CT	acceptor_gain	1.0000
4:41746334:C:CT	acceptor_gain	1.0000
4:41746335:G:T	acceptor_gain	1.0000
4:41746347:G:T	acceptor_gain	1.0000
4:41746354:C:CT	acceptor_gain	1.0000
4:41746355:A:T	acceptor_gain	1.0000
4:41747346:TA:T	donor_loss	1.0000
4:41747347:A:AC	donor_gain	1.0000
4:41747347:A:C	donor_loss	1.0000
4:41747348:C:CC	donor_gain	1.0000
4:41747348:C:CG	donor_loss	1.0000
4:41747534:GAA:G	acceptor_gain	1.0000
4:41747537:C:CC	acceptor_gain	1.0000
4:41746318:CACAC:C	acceptor_gain	0.9900
4:41746319:ACAC:A	acceptor_gain	0.9900
4:41746320:CAC:C	acceptor_gain	0.9900
4:41746320:CACC:C	acceptor_gain	0.9900
4:41746322:CCTGG:C	acceptor_loss	0.9900
4:41746329:C:T	acceptor_gain	0.9900
4:41746330:A:T	acceptor_gain	0.9900
4:41746346:C:CT	acceptor_gain	0.9900
4:41746348:G:C	acceptor_gain	0.9900
4:41746348:G:GC	acceptor_gain	0.9900
4:41747532:AGGAA:A	acceptor_gain	0.9900
4:41747533:GGAA:G	acceptor_gain	0.9900
4:41747533:GGAAC:G	acceptor_loss	0.9900
4:41747535:AA:A	acceptor_gain	0.9900
4:41747536:AC:A	acceptor_loss	0.9900
4:41747537:C:CA	acceptor_loss	0.9900
4:41747538:T:G	acceptor_loss	0.9900

AlphaMissense

2022 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:41746287:C:A	K155N	1.000
4:41746287:C:G	K155N	1.000
4:41746288:T:A	K155M	1.000
4:41746289:T:C	K155E	1.000
4:41746291:C:G	R154P	1.000
4:41746291:C:T	R154H	1.000
4:41746292:G:A	R154C	1.000
4:41746292:G:C	R154G	1.000
4:41746292:G:T	R154S	1.000
4:41746293:A:C	F153L	1.000
4:41746293:A:T	F153L	1.000
4:41746294:A:G	F153S	1.000
4:41746295:A:G	F153L	1.000
4:41746296:C:A	K152N	1.000
4:41746296:C:G	K152N	1.000
4:41746297:T:A	K152M	1.000
4:41746298:T:C	K152E	1.000
4:41746298:T:G	K152Q	1.000
4:41746300:G:A	A151V	1.000
4:41746300:G:T	A151D	1.000
4:41746301:C:G	A151P	1.000
4:41746303:C:G	R150P	1.000
4:41746303:C:T	R150H	1.000
4:41746304:G:A	R150C	1.000
4:41746304:G:C	R150G	1.000
4:41746304:G:T	R150S	1.000
4:41746306:C:A	R149L	1.000
4:41746306:C:G	R149P	1.000
4:41746307:G:A	R149C	1.000
4:41746307:G:C	R149G	1.000

dbSNP variants (sampled 300 via entrez): RS1000113801 (4:41744397 A>G), RS1000518405 (4:41750049 G>A,C,T), RS1000549328 (4:41744699 T>G), RS1000588097 (4:41749574 T>G), RS1001283861 (4:41743938 C>A), RS1001445436 (4:41750226 T>C), RS1001876854 (4:41750407 A>G), RS1001913562 (4:41746831 A>C), RS1002409006 (4:41747087 A>G,T), RS1002863835 (4:41748812 T>C), RS1002992007 (4:41745001 T>A,G), RS1003452907 (4:41747339 G>A,T), RS1003891702 (4:41747653 C>A,T), RS1004485085 (4:41746785 G>T), RS1004518481 (4:41750156 A>T)

Disease associations

OMIM: gene MIM:603851 | disease phenotypes: MIM:209880, MIM:613013, MIM:167000, MIM:142623

GenCC curated gene-disease

Disease	Classification	Inheritance
central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease	Definitive	Autosomal dominant
neuroblastoma, susceptibility to, 2	Definitive	Autosomal dominant
Haddad syndrome	Definitive	Autosomal dominant
congenital central hypoventilation syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Haddad syndrome	Definitive	AD
central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease	Definitive	AD

Mondo (9): Haddad syndrome (MONDO:0020493), hereditary neoplastic syndrome (MONDO:0015356), central hypoventilation syndrome, congenital (MONDO:0800031), neuroblastoma, susceptibility to, 2 (MONDO:0700041), central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease (MONDO:0800026), ovarian cancer (MONDO:0008170), Hirschsprung disease (MONDO:0018309), Hirschsprung disease-ganglioneuroblastoma syndrome (MONDO:0013082), (MONDO:0008852)

Orphanet (7): Haddad syndrome (Orphanet:99803), Inherited cancer-predisposing syndrome (Orphanet:140162), Congenital central hypoventilation syndrome (Orphanet:661), Neuroblastoma (Orphanet:635), Rare ovarian cancer (Orphanet:213500), Hirschsprung disease (Orphanet:388), Hirschsprung disease-ganglioneuroblastoma syndrome (Orphanet:2151)

HPO phenotypes

78 total (30 of 78 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000407	Sensorineural hearing impairment
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000520	Proptosis
HP:0000615	Abnormal pupil morphology
HP:0000737	Irritability
HP:0000822	Hypertension
HP:0000975	Hyperhidrosis
HP:0001017	Anemic pallor
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001336	Myoclonus
HP:0001482	Subcutaneous nodule
HP:0001508	Failure to thrive
HP:0001518	Small for gestational age
HP:0001522	Death in infancy
HP:0001558	Decreased fetal movement
HP:0001561	Polyhydramnios
HP:0001562	Oligohydramnios
HP:0001657	Prolonged QT interval
HP:0001824	Weight loss
HP:0001873	Thrombocytopenia
HP:0001892	Abnormal bleeding
HP:0001903	Anemia
HP:0001928	Abnormality of coagulation

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST003381_1	Bone mineral density (femoral neck)	1.000000e-07
GCST003764_5	Hirschsprung disease	6.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007785	femoral neck bone mineral density

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D006627	Hirschsprung Disease	C06.198.439; C06.405.469.158.701.439; C16.131.314.439
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
D010051	Ovarian Neoplasms	C04.588.322.455; C12.050.351.500.056.630.705; C12.050.351.937.418.685; C12.100.250.056.630.705; C12.900.418.685; C19.344.410; C19.391.630.705
C538119	Hirschsprung disease ganglioneuroblastoma (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, decreases methylation	4
Benzo(a)pyrene	decreases expression, affects methylation	2
Tretinoin	decreases expression, increases expression	2
bisphenol A	increases methylation	1
arsenite	increases methylation	1
beta-methylcholine	affects expression	1
CGP 52608	affects binding, increases reaction	1
entinostat	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Decitabine	increases expression, decreases methylation	1
Arsenic Trioxide	decreases expression	1
Vorinostat	decreases expression	1
Acetaminophen	decreases expression	1
Dexamethasone	affects expression	1
Mercury	increases expression	1
Aflatoxin B1	decreases methylation	1

Cellosaurus cell lines

13 cell lines: 10 induced pluripotent stem cell, 3 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A5I3	SEES3-1V human PHOX2B, clone1	Embryonic stem cell	Male
CVCL_A5I4	SEES3-1V human PHOX2B, clone2	Embryonic stem cell	Male
CVCL_A5I5	SEES3-1V human PHOX2B, clone3	Embryonic stem cell	Male
CVCL_A9XA	BGUi004-A	Induced pluripotent stem cell	Male
CVCL_A9XB	BGUi005-A	Induced pluripotent stem cell	Male
CVCL_C0ID	UMILi027-A	Induced pluripotent stem cell	Female
CVCL_C0IE	UMILi028-A	Induced pluripotent stem cell	Female
CVCL_C9XT	HPS2413	Induced pluripotent stem cell	Female
CVCL_C9XU	HPS2414	Induced pluripotent stem cell	Female
CVCL_C9XV	HPS2415	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00190697	PHASE4	COMPLETED	A Study of LY353381 (Arzoxifene) for Patients Who Benefitted From This Drug in Other Oncology Trials and Wished to Continue Treatment
NCT00277160	PHASE4	COMPLETED	A Study of Primary Prophylaxis With Neulasta (Pegfilgrastim) Versus Secondary Prophylaxis After Chemotherapy in Elderly Subjects (>/= 65 Years Old) With Cancer
NCT00727961	PHASE4	COMPLETED	A Study to Evaluate Efficacy and Tolerance of Caelyx in Patients With Epithelial Ovarian Cancer. (Study P04072)(COMPLETED)
NCT00740116	PHASE4	COMPLETED	Tranexamic Acid in Surgery of Advanced Ovarian Cancer
NCT00817479	PHASE4	COMPLETED	Tumor Gene Expression in Women With Ovarian Cancer
NCT01432015	PHASE4	COMPLETED	Fosaprepitant Versus Aprepitant in the Prevention of Chemotherapy Induced Nausea and Vomiting
NCT01706120	PHASE4	UNKNOWN	Study of Clinical and Biological Prognostic Factors in Patients With Ovarian Cancer Receiving Carboplatin +Paclitaxel With Bevacizumab
NCT01932125	PHASE4	COMPLETED	An Interventional Study of Avastin (Bevacizumab) in Patients With Advanced/Metastatic Epithelial Ovarian Cancer, Fallopian Tube Cancer or Primary Peritoneal Cancer
NCT01953107	PHASE4	COMPLETED	Oral Iron vs. Placebo in Newly Diagnosed Gynecologic Oncology Patients Who Are Surgical Candidates.
NCT02035345	PHASE4	TERMINATED	Slowed Carboplatin Infusion for Ovarian Cancer Patients Receiving Carboplatin Re-Treatment
NCT02243059	PHASE4	WITHDRAWN	Magnetic Resonance Imaging for Lymph Node Staging in Ovarian Cancer
NCT03164980	PHASE4	TERMINATED	QoL-Comparison Between Trabectedin/PLD and Pt-based Therapy in Patients With Pt-sensitive Recurrent Ovarian Cancer
NCT03384511	PHASE4	COMPLETED	The Use of 18F-ALF-NOTA-PRGD2 PET/CT Scan to Predict the Efficacy and Adverse Events of Apatinib in Malignancies.
NCT03543462	PHASE4	COMPLETED	Diaphragmatic Resection And Gynecological Ovarian Neoplasm
NCT03752216	PHASE4	COMPLETED	NIraparib and Quality of LifE is a Longitudinal Study Evaluating in Real Life the Tolerability of Niraparib.
NCT03858166	PHASE4	TERMINATED	Efficacy and Safety of PEG-rhG-CSF Secondary Prophylaxis vs. Therapeutic Administration in Patients With Ovarian Cancer
NCT04024254	PHASE4	COMPLETED	A Study of Serum Folate Levels in Patients Treated With Olaparib
NCT04330040	PHASE4	COMPLETED	Prospective Multicentre Phase-IV Clinical Trial of Olaparib in Indian Patients With Ovarian and Metastatic Breast Cancer
NCT04352439	PHASE4	COMPLETED	Aspirin for Prevention of Venous Thromboembolism Among Ovarian Cancer Patients Receiving Neoadjuvant Chemotherapy
NCT05187208	PHASE4	UNKNOWN	PARP Inhibitor Oral Maintenance in Low-Risk Ovarian Cancer
NCT05606692	PHASE4	RECRUITING	Influences of Propofol and Sevoflurane Anesthesia in Ovarian Cancer (Anesthetics)
NCT05926336	PHASE4	RECRUITING	The Effects of Using Different Anesthetics on the Prognosis of Primary Tumors and Its Mechanism of Action
NCT06412120	PHASE4	RECRUITING	Study Evaluating Safety, Tolerability, and Metabolism of Niraparib
NCT06871787	PHASE4	NOT_YET_RECRUITING	Near-Infrared Fluorescence Imaging With Indocyanine Green to Evaluate Bowel Anastomoses in Gynecologic Oncology Surgery
NCT06887933	PHASE4	NOT_YET_RECRUITING	A Trial to Evaluate the Safety of Niraparib Tablets in Adult Female Participants With Advanced or Relapsed Epithelial Ovarian Cancer
NCT07469202	PHASE4	NOT_YET_RECRUITING	CYTALUX Dose Extension Study
NCT00001806	PHASE3	COMPLETED	Methods in Education for Breast Cancer Genetics
NCT00002477	PHASE3	UNKNOWN	Adjuvant Chemotherapy Compared With Observation in Treating Patients With Resected Early Stage Ovarian Epithelial Cancer
NCT00002568	PHASE3	COMPLETED	Combination Chemotherapy With or Without Surgery in Treating Patients With Stage III Ovarian Epithelial Cancer
NCT00002641	PHASE3	COMPLETED	Surgery With or Without Chemotherapy in Treating Patients With Soft Tissue Sarcoma
NCT00002717	PHASE3	COMPLETED	Paclitaxel and Cisplatin in Treating Patients With Stage III or Stage IV Ovarian Cancer or Primary Peritoneal Cancer
NCT00002764	PHASE3	COMPLETED	Surgery With or Without Combination Chemotherapy in Treating Patients With Lung Metastases From Soft Tissue Sarcoma
NCT00002819	PHASE3	TERMINATED	Chemotherapy With or Without Peripheral Stem Cell Transplantation in Treating Patients With Persistent Ovarian Epithelial Cancer
NCT00002894	PHASE3	COMPLETED	Platinum-based Chemotherapy With or Without Paclitaxel in Treating Patients With Relapsed Ovarian Cancer
NCT00002895	PHASE3	COMPLETED	Early Chemotherapy Based on CA 125 Level Alone Compared With Delayed Chemotherapy in Treating Patients With Recurrent Ovarian Epithelial , Fallopian Tube, or Primary Peritoneal Cancer
NCT00003120	PHASE3	COMPLETED	S9701 Paclitaxel in Treating Patients With Advanced Ovarian, Fallopian Tube, or Primary Peritoneal Cancer in Remission
NCT00003214	PHASE3	COMPLETED	Chemosensitivity Testing to Assign Treatment for Patients With Stage III or Stage IV Ovarian Cancer
NCT00003322	PHASE3	COMPLETED	Combination Chemotherapy in Treating Patients With Primary Peritoneal or Stage III Epithelial Ovarian Cancer
NCT00003636	PHASE3	COMPLETED	Chemotherapy Plus Surgery in Treating Patients With Stage III or Stage IV Ovarian, Peritoneal, or Fallopian Tube Cancer
NCT00003644	PHASE3	COMPLETED	Carboplatin Plus Paclitaxel With or Without Continued Low-Dose Paclitaxel in Treating Patients With Early-Stage Ovarian Cancer