Biology:PHOX2B
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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.[1]
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.[2][3][4][5]
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.[6]
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.
References
- ↑ "Entrez Gene: paired-like homeobox 2b". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=8929.
- ↑ Bielle, Franck; Fréneaux, Paul; Jeanne-Pasquier, Corinne; Maran-Gonzalez, Aurélie; Rousseau, Audrey; Lamant, Laurence; Paris, Régine; Pierron, Gaëlle et al. (2012). "PHOX2B Immunolabeling". The American Journal of Surgical Pathology 36 (8): 1141–1149. doi:10.1097/PAS.0b013e31825a6895. PMID 22790854.
- ↑ Hata, Jessica L.; Correa, Hernan; Krishnan, Chandra; Esbenshade, Adam J.; Black, Jennifer O.; Chung, Dai H.; Mobley, Bret C. (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.
- ↑ Hung, Yin P.; Lee, John P.; Bellizzi, Andrew M.; Hornick, Jason L. (2017). "PHOX2B reliably distinguishes neuroblastoma among small round blue cell tumours". Histopathology 71 (5): 786–794. doi:10.1111/his.13288. PMID 28640941.
- ↑ Warren, Mikako; Matsuno, Ryosuke; Tran, Henry; Shimada, Hiroyuki (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.
- ↑ Hata et al. (2015).
Further reading
- "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.". Am. J. Gastroenterol. 104 (3): 665–72. 2009. doi:10.1038/ajg.2008.65. PMID 19262523.
- "Pediatric disorders with autonomic dysfunction: what role for PHOX2B?". Pediatr. Res. 58 (1): 1–6. 2005. doi:10.1203/01.PDR.0000166755.29277.C4. PMID 15901893.
- "Association analysis of the PHOX2B gene with Hirschsprung disease in the Han Chinese population of Southeastern China.". J. Pediatr. Surg. 44 (9): 1805–11. 2009. doi:10.1016/j.jpedsurg.2008.12.009. PMID 19735829.
- "Later-onset congenital central hypoventilation syndrome due to a heterozygous 24-polyalanine repeat expansion mutation in the PHOX2B gene.". Acta Paediatr. 98 (1): 192–5. 2009. doi:10.1111/j.1651-2227.2008.01039.x. PMID 18798833.
- "Effects of transcription factors Phox2 on expression of norepinephrine transporter and dopamine beta-hydroxylase in SK-N-BE(2)C cells.". J. Neurochem. 110 (5): 1502–13. 2009. doi:10.1111/j.1471-4159.2009.06260.x. PMID 19573018.
- "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. 2009. doi:10.1186/1471-2164-10-8. PMID 19128492.
- "Comparison of PHOX2B testing methods in the diagnosis of congenital central hypoventilation syndrome and mosaic carriers.". Diagn. Mol. Pathol. 19 (4): 224–31. 2010. doi:10.1097/PDM.0b013e3181eb92ff. PMID 21051998.
- "Post-mortem pathologic and genetic studies in "dead in bed syndrome" cases in type 1 diabetes mellitus.". Hum. Pathol. 41 (3): 392–400. 2010. doi:10.1016/j.humpath.2009.08.020. PMID 20004937.
- "Molecular pathogenesis of peripheral neuroblastic tumors.". Oncogene 29 (11): 1566–79. 2010. doi:10.1038/onc.2009.518. PMID 20101209.
- "PHOX2A and PHOX2B genes are highly co-expressed in human neuroblastoma.". Int. J. Oncol. 33 (5): 985–91. 2008. doi:10.3892/ijo_00000086. PMID 18949361.
- "Congenital Central Hypoventilation Syndrome due to PHOX2b gene defects: inheritance from asymptomatic parents.". Klin Padiatr 221 (5): 286–9. 2009. doi:10.1055/s-0029-1220941. PMID 19707990.
- "Polyalanine expansion of PHOX2B in congenital central hypoventilation syndrome: rs17884724:A>C is associated with 7-alanine expansion.". J. Hum. Genet. 55 (1): 4–7. 2010. doi:10.1038/jhg.2009.109. PMID 19881470.
- "PHOX2B mutation-confirmed congenital central hypoventilation syndrome in a Chinese family: presentation from newborn to adulthood.". Chest 135 (2): 537–44. 2009. doi:10.1378/chest.08-1664. PMID 19201717.
- "Interaction between PHOX2B and CREBBP mediates synergistic activation: mechanistic implications of PHOX2B mutants.". Hum. Mutat. 30 (4): 655–60. 2009. doi:10.1002/humu.20929. PMID 19191321.
- "In Vitro studies of non poly alanine PHOX2B mutations argue against a loss-of-function mechanism for congenital central hypoventilation.". Hum. Mutat. 30 (2): E421-31. 2009. doi:10.1002/humu.20923. PMID 19058226.
- "Defective respiratory rhythmogenesis and loss of central chemosensitivity in Phox2b mutants targeting retrotrapezoid nucleus neurons.". J. Neurosci. 29 (47): 14836–46. 2009. doi:10.1523/JNEUROSCI.2623-09.2009. PMID 19940179.
- "Rare occurrence of PHOX2b mutations in sporadic neuroblastomas.". J. Pediatr. Hematol. Oncol. 30 (10): 728–32. 2008. doi:10.1097/MPH.0b013e3181772141. PMID 19011468.
- "PHOX2B immunolocalization of the candidate human retrotrapezoid nucleus.". Pediatr. Dev. Pathol. 13 (4): 291–9. 2010. doi:10.2350/09-07-0682-OA.1. PMID 19888871.
- "A candidate gene study of obstructive sleep apnea in European Americans and African Americans.". Am. J. Respir. Crit. Care Med. 182 (7): 947–53. 2010. doi:10.1164/rccm.201002-0192OC. PMID 20538960.
- "Association of linear growth impairment in pediatric Crohn's disease and a known height locus: a pilot study.". Ann. Hum. Genet. 74 (6): 489–97. 2010. doi:10.1111/j.1469-1809.2010.00606.x. PMID 20846217.
External links
- GeneReviews/NCBI/NIH/UW entry on Congenital Central Hypoventilation Syndrome
- Phox2b+protein at the US National Library of Medicine Medical Subject Headings (MeSH)
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