PHOX2B
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| Location (UCSC) | Chr 4: 41.74 – 41.75 Mb | Chr 5: 67.25 – 67.26 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
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Paired-like homeobox 2b (PHOX2B), also known as neuroblastoma Phox (NBPhox), is a
chromosome 4.[5]
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.[6][7][8][9]
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.[10]
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
- ^ a b c GRCh38: Ensembl release 89: ENSG00000109132 - Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000012520 - Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Entrez Gene: paired-like homeobox 2b".
- S2CID 25924210.
- PMID 25822764.
- S2CID 19123236.
- S2CID 3302863.
- ^ Hata et al. (2015).
Further reading
- Glas J, Seiderer J, Pasciuto G, et al. (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". Am. J. Gastroenterol. 104 (3): 665–72. S2CID 7144509.
- Gaultier C, Trang H, Dauger S, Gallego J (2005). "Pediatric disorders with autonomic dysfunction: what role for PHOX2B?". Pediatr. Res. 58 (1): 1–6. PMID 15901893.
- Liu CP, Li XG, Lou JT, et al. (2009). "Association analysis of the PHOX2B gene with Hirschsprung disease in the Han Chinese population of Southeastern China". J. Pediatr. Surg. 44 (9): 1805–11. PMID 19735829.
- Repetto GM, Corrales RJ, Abara SG, et al. (2009). "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. S2CID 4979994.
- Fan Y, Huang J, Kieran N, Zhu MY (2009). "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. PMID 19573018.
- McGaughey DM, Stine ZE, Huynh JL, et al. (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. PMID 19128492.
- Jennings LJ, Yu M, Zhou L, et al. (2010). "Comparison of PHOX2B testing methods in the diagnosis of congenital central hypoventilation syndrome and mosaic carriers". Diagn. Mol. Pathol. 19 (4): 224–31. S2CID 10071866.
- Tu E, Bagnall RD, Duflou J, et al. (2010). "Post-mortem pathologic and genetic studies in "dead in bed syndrome" cases in type 1 diabetes mellitus". Hum. Pathol. 41 (3): 392–400. PMID 20004937.
- Janoueix-Lerosey I, Schleiermacher G, Delattre O (2010). "Molecular pathogenesis of peripheral neuroblastic tumors". Oncogene. 29 (11): 1566–79. PMID 20101209.
- Longo L, Borghini S, Schena F, et al. (2008). "PHOX2A and PHOX2B genes are highly co-expressed in human neuroblastoma". Int. J. Oncol. 33 (5): 985–91. PMID 18949361.
- Hammel M, Klein M, Trips T, et al. (2009). "Congenital Central Hypoventilation Syndrome due to PHOX2b gene defects: inheritance from asymptomatic parents". Klin Padiatr. 221 (5): 286–9. S2CID 206295649.
- Arai H, Otagiri T, Sasaki A, et al. (2010). "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. PMID 19881470.
- Lee P, Su YN, Yu CJ, et al. (2009). "PHOX2B mutation-confirmed congenital central hypoventilation syndrome in a Chinese family: presentation from newborn to adulthood". Chest. 135 (2): 537–44. PMID 19201717.
- Wu HT, Su YN, Hung CC, et al. (2009). "Interaction between PHOX2B and CREBBP mediates synergistic activation: mechanistic implications of PHOX2B mutants". Hum. Mutat. 30 (4): 655–60. S2CID 22257861.
- Trochet D, Mathieu Y, Pontual L, et al. (2009). "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. S2CID 10167662.
- Dubreuil V, Thoby-Brisson M, Rallu M, et al. (2009). "Defective respiratory rhythmogenesis and loss of central chemosensitivity in Phox2b mutants targeting retrotrapezoid nucleus neurons". J. Neurosci. 29 (47): 14836–46. PMID 19940179.
- Serra A, Häberle B, König IR, et al. (2008). "Rare occurrence of PHOX2b mutations in sporadic neuroblastomas". J. Pediatr. Hematol. Oncol. 30 (10): 728–32. S2CID 32426671.
- Rudzinski E, Kapur RP (2010). "PHOX2B immunolocalization of the candidate human retrotrapezoid nucleus". Pediatr. Dev. Pathol. 13 (4): 291–9. S2CID 34088649.
- Larkin EK, Patel SR, Goodloe RJ, et al. (2010). "A candidate gene study of obstructive sleep apnea in European Americans and African Americans". Am. J. Respir. Crit. Care Med. 182 (7): 947–53. PMID 20538960.
- Lee JJ, Essers JB, Kugathasan S, et al. (2010). "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. 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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