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PHOX2B
Identifiers
Aliases	PHOX2B, NBLST2, NBPhox, PMX2B, paired like homeobox 2b, CCHS
External IDs	OMIM: 603851; MGI: 1100882; HomoloGene: 68371; GeneCards: PHOX2B; OMA:PHOX2B - orthologs
Gene location (Human) Chr. Chromosome 4 (human) Band 4p13 Start 41,744,082 bp End 41,748,725 bp
Gene location (Mouse) Chr. Chromosome 5 (mouse) Band 5 C3.1|5 35.95 cM Start 67,251,742 bp End 67,256,644 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in muscle layer of sigmoid colon buccal mucosa cell dorsal motor nucleus of vagus nerve inferior olivary nucleus rectum transverse colon appendix small intestine right adrenal gland duodenum Top expressed in migratory enteric neural crest cell external carotid artery pelvic ganglion enteric nervous system internal carotid artery adrenal gland facial motor nucleus female urethra medial vestibular nucleus male urethra More reference expression data BioGPS n/a
Gene ontology Molecular function sequence-specific DNA binding RNA polymerase II transcription regulatory region sequence-specific DNA binding RNA polymerase II cis-regulatory region sequence-specific DNA binding DNA binding DNA-binding transcription activator activity, RNA polymerase II-specific DNA-binding transcription factor activity, RNA polymerase II-specific Cellular component nucleus nucleoplasm Biological process negative regulation of cell population proliferation glial cell differentiation respiratory system development positive regulation of G2/M transition of mitotic cell cycle medullary reticular formation development transcription, DNA-templated parasympathetic nervous system development regulation of respiratory gaseous exchange by nervous system process noradrenergic neuron development cellular response to BMP stimulus multicellular organism development neural crest cell migration involved in autonomic nervous system development hindbrain tangential cell migration sympathetic nervous system development skeletal muscle cell differentiation enteric nervous system development retrotrapezoid nucleus neuron differentiation regulation of gene expression positive regulation of neuron differentiation brainstem development inner ear development cell development regulation of transcription, DNA-templated sympathetic ganglion development negative regulation of neuron differentiation cell differentiation in hindbrain autonomic nervous system development efferent axon development in a lateral line nerve neuron differentiation neuron migration dopaminergic neuron differentiation noradrenergic neuron differentiation positive regulation of transcription by RNA polymerase II transcription by RNA polymerase II positive regulation of cold-induced thermogenesis nervous system development Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 8929 18935 Ensembl ENSG00000109132 ENSMUSG00000012520 UniProt Q99453 O35690 RefSeq (mRNA) NM_003924 NM_008888 RefSeq (protein) NP_003915 NP_032914 Location (UCSC) Chr 4: 41.74 – 41.75 Mb Chr 5: 67.25 – 67.26 Mb PubMed search
Wikidata
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Paired-like homeobox 2b (PHOX2B), also known as neuroblastoma Phox (NBPhox), is a protein that in humans is encoded by the PHOX2B gene located on chromosome 4.

It codes for a homeodomain transcription factor. It is expressed exclusively in the nervous system, in most neurons that control the viscera (cardiovascular, digestive and respiratory systems). It is also required for their differentiation.

Immunohistochemistry

Essential for the differentiation and survival of sympathetic neurons and chromaffin cells, the transcription factor PHOX2B is highly specific for the peripheral autonomic nervous system. Neuroblasts are derived from sympathoadrenal lineage neural crest cells and therefore require and constitutively express PHOX2B. PHOX2B immunohistochemical staining, as a marker of neural crest derivation, has been shown to be sensitive and specific for undifferentiated neuroblastoma, enabling identification where other markers fail to recognize neuroblastoma among various different small round blue cell tumors of childhood.

The diagnostic utility of PHOX2B staining extends to later stages of differentiation. Its strength and specificity can detect the small foci of neuroblastic tumors metastatic to the bone marrow, an identification critical for determining disease staging. PHOX2B staining also overcomes frequent obstacles to neuroblastoma detection in post-treatment samples, which frequently exhibit dense fibrosis, prominent inflammatory infiltrates, and/or diffuse calcification.

Pathology

Mutations in human PHOX2B cause a rare disease of the visceral nervous system (dysautonomia): congenital central hypoventilation syndrome (associated with respiratory arrests during sleep and, occasionally, wakefulness), Hirschsprung's disease (partial agenesis of the enteric nervous system), ROHHAD, and tumours of the sympathetic ganglia. In most people, Exon 3 of the gene contains a sequence of 20 polyalanine repeats. An increase in the number of repeats is associated with congenital central hypoventilation syndrome. There may also be other pathogenic mutations further along the gene.

Research into Phox2B

Organisations involved in researching Phox2B include those concerned with Congenitial Central Hypoventilation Syndrome. These include Keep Me Breathing based in the UK and The CCHS Network based in the USA. The CCHS Network held a scientific conference in September 2023, which covered significant research into Phox2B and CCHS with Keep Me Breathing presenting, too.

References

1. ^ GRCh38: Ensembl release 89: ENSG00000109132 – Ensembl, May 2017
2. ^ GRCm38: Ensembl release 89: ENSMUSG00000012520 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: paired-like homeobox 2b".
6. Bielle F, Fréneaux P, Jeanne-Pasquier C, Maran-Gonzalez A, Rousseau A, Lamant L, et al. (August 2012). "PHOX2B immunolabeling: a novel tool for the diagnosis of undifferentiated neuroblastomas among childhood small round blue-cell tumors". The American Journal of Surgical Pathology. 36 (8): 1141–1149. doi:10.1097/PAS.0b013e31825a6895. PMID 22790854. S2CID 25924210.
7. Hata JL, Correa H, Krishnan C, Esbenshade AJ, Black JO, Chung DH, et al. (April 2015). "Diagnostic utility of PHOX2B in primary and treated neuroblastoma and in neuroblastoma metastatic to the bone marrow". Archives of Pathology & Laboratory Medicine. 139 (4): 543–546. doi:10.5858/arpa.2014-0255-OA. PMID 25822764.
8. Hung YP, Lee JP, Bellizzi AM, Hornick JL (November 2017). "PHOX2B reliably distinguishes neuroblastoma among small round blue cell tumours". Histopathology. 71 (5): 786–794. doi:10.1111/his.13288. PMID 28640941. S2CID 19123236.
9. Warren M, Matsuno R, Tran H, Shimada H (March 2018). "Utility of Phox2b immunohistochemical stain in neural crest tumours and non-neural crest tumours in paediatric patients". Histopathology. 72 (4): 685–696. doi:10.1111/his.13412. PMID 28986989. S2CID 3302863.
10. Hata et al. (2015).
11. "CCHS for Professionals – Keep Me Breathing". Retrieved 2024-08-09.
12. "2023 CCHS Science Conference". CCHS Network. Retrieved 2024-08-09.

Further reading

• Glas J, Seiderer J, Pasciuto G, Tillack C, Diegelmann J, Pfennig S, et al. (March 2009). "rs224136 on chromosome 10q21.1 and variants in PHOX2B, NCF4, and FAM92B are not major genetic risk factors for susceptibility to Crohn's disease in the German population". The American Journal of Gastroenterology. 104 (3): 665–672. doi:10.1038/ajg.2008.65. PMID 19262523. S2CID 7144509.
• Gaultier C, Trang H, Dauger S, Gallego J (July 2005). "Pediatric disorders with autonomic dysfunction: what role for PHOX2B?". Pediatric Research. 58 (1): 1–6. doi:10.1203/01.PDR.0000166755.29277.C4. PMID 15901893.
• Liu CP, Li XG, Lou JT, Xue Y, Luo CF, Zhou XW, et al. (September 2009). "Association analysis of the PHOX2B gene with Hirschsprung disease in the Han Chinese population of Southeastern China". Journal of Pediatric Surgery. 44 (9): 1805–1811. doi:10.1016/j.jpedsurg.2008.12.009. PMID 19735829.
• Repetto GM, Corrales RJ, Abara SG, Zhou L, Berry-Kravis EM, Rand CM, et al. (January 2009). "Later-onset congenital central hypoventilation syndrome due to a heterozygous 24-polyalanine repeat expansion mutation in the PHOX2B gene". Acta Paediatrica. 98 (1): 192–195. doi:10.1111/j.1651-2227.2008.01039.x. PMID 18798833. S2CID 4979994.
• Fan Y, Huang J, Kieran N, Zhu MY (September 2009). "Effects of transcription factors Phox2 on expression of norepinephrine transporter and dopamine beta-hydroxylase in SK-N-BE(2)C cells". Journal of Neurochemistry. 110 (5): 1502–1513. doi:10.1111/j.1471-4159.2009.06260.x. PMC 9339151. PMID 19573018.
• McGaughey DM, Stine ZE, Huynh JL, Vinton RM, McCallion AS (January 2009). "Asymmetrical distribution of non-conserved regulatory sequences at PHOX2B is reflected at the ENCODE loci and illuminates a possible genome-wide trend". BMC Genomics. 10: 8. doi:10.1186/1471-2164-10-8. PMC 2630312. PMID 19128492.
• Jennings LJ, Yu M, Zhou L, Rand CM, Berry-Kravis EM, Weese-Mayer DE (December 2010). "Comparison of PHOX2B testing methods in the diagnosis of congenital central hypoventilation syndrome and mosaic carriers". Diagnostic Molecular Pathology. 19 (4): 224–231. doi:10.1097/PDM.0b013e3181eb92ff. PMID 21051998. S2CID 10071866.
• Tu E, Bagnall RD, Duflou J, Lynch M, Twigg SM, Semsarian C (March 2010). "Post-mortem pathologic and genetic studies in "dead in bed syndrome" cases in type 1 diabetes mellitus". Human Pathology. 41 (3): 392–400. doi:10.1016/j.humpath.2009.08.020. PMID 20004937.
• Janoueix-Lerosey I, Schleiermacher G, Delattre O (March 2010). "Molecular pathogenesis of peripheral neuroblastic tumors". Oncogene. 29 (11): 1566–1579. doi:10.1038/onc.2009.518. PMID 20101209.
• Longo L, Borghini S, Schena F, Parodi S, Albino D, Bachetti T, et al. (November 2008). "PHOX2A and PHOX2B genes are highly co-expressed in human neuroblastoma". International Journal of Oncology. 33 (5): 985–991. doi:10.3892/ijo_00000086. PMID 18949361.
• Hammel M, Klein M, Trips T, Priessmann H, Ankermann T, Holzinger A (September 2009). "Congenital Central Hypoventilation Syndrome due to PHOX2b gene defects: inheritance from asymptomatic parents". Klinische Padiatrie. 221 (5): 286–289. doi:10.1055/s-0029-1220941. PMID 19707990. S2CID 206295649.
• Arai H, Otagiri T, Sasaki A, Umetsu K, Hayasaka K (January 2010). "Polyalanine expansion of PHOX2B in congenital central hypoventilation syndrome: rs17884724:A>C is associated with 7-alanine expansion". Journal of Human Genetics. 55 (1): 4–7. doi:10.1038/jhg.2009.109. PMID 19881470.
• Lee P, Su YN, Yu CJ, Yang PC, Wu HD (February 2009). "PHOX2B mutation-confirmed congenital central hypoventilation syndrome in a Chinese family: presentation from newborn to adulthood". Chest. 135 (2): 537–544. doi:10.1378/chest.08-1664. PMID 19201717.
• Wu HT, Su YN, Hung CC, Hsieh WS, Wu KJ (April 2009). "Interaction between PHOX2B and CREBBP mediates synergistic activation: mechanistic implications of PHOX2B mutants". Human Mutation. 30 (4): 655–660. doi:10.1002/humu.20929. PMID 19191321. S2CID 22257861.
• Trochet D, Mathieu Y, Pontual L, Savarirayan R, Munnich A, Brunet JF, et al. (February 2009). "In Vitro studies of non poly alanine PHOX2B mutations argue against a loss-of-function mechanism for congenital central hypoventilation". Human Mutation. 30 (2): E421 – E431. doi:10.1002/humu.20923. PMID 19058226. S2CID 10167662.
• Dubreuil V, Thoby-Brisson M, Rallu M, Persson K, Pattyn A, Birchmeier C, et al. (November 2009). "Defective respiratory rhythmogenesis and loss of central chemosensitivity in Phox2b mutants targeting retrotrapezoid nucleus neurons". The Journal of Neuroscience. 29 (47): 14836–14846. doi:10.1523/JNEUROSCI.2623-09.2009. PMC 6665996. PMID 19940179.
• Serra A, Häberle B, König IR, Kappler R, Suttorp M, Schackert HK, et al. (October 2008). "Rare occurrence of PHOX2b mutations in sporadic neuroblastomas". Journal of Pediatric Hematology/Oncology. 30 (10): 728–732. doi:10.1097/MPH.0b013e3181772141. PMID 19011468. S2CID 32426671.
• Rudzinski E, Kapur RP (2010). "PHOX2B immunolocalization of the candidate human retrotrapezoid nucleus". Pediatric and Developmental Pathology. 13 (4): 291–299. doi:10.2350/09-07-0682-OA.1. PMID 19888871. S2CID 34088649.
• Larkin EK, Patel SR, Goodloe RJ, Li Y, Zhu X, Gray-McGuire C, et al. (October 2010). "A candidate gene study of obstructive sleep apnea in European Americans and African Americans". American Journal of Respiratory and Critical Care Medicine. 182 (7): 947–953. doi:10.1164/rccm.201002-0192OC. PMC 2970865. PMID 20538960.
• Lee JJ, Essers JB, Kugathasan S, Escher JC, Lettre G, Butler JL, et al. (November 2010). "Association of linear growth impairment in pediatric Crohn's disease and a known height locus: a pilot study". Annals of Human Genetics. 74 (6): 489–497. doi:10.1111/j.1469-1809.2010.00606.x. PMC 2955808. PMID 20846217.

External links

• GeneReviews/NCBI/NIH/UW entry on Congenital Central Hypoventilation Syndrome
• Phox2b+protein at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

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