PHOX2B

PHOX2B
Identifikatori
Aliasi	PHOX2B
Vanjski ID-jevi	OMIM: 603851 MGI: 1100882 HomoloGene: 68371 GeneCards: PHOX2B
Lokacija gena (čovjek)
Hrom.	Hromosom 4 (čovjek)
Kraj	41,748,725 bp
Lokacija gena (miš)
Hrom.	Hromosom 5 (miš)
Kraj	67,256,644 bp
Ontologija gena
Molekularna funkcija	• sequence-specific DNA binding; • RNA polymerase II transcription regulatory region sequence-specific DNA binding; • GO:0000980 RNA polymerase II cis-regulatory region sequence-specific DNA binding; • vezivanje sa DNK; • GO:0001077, GO:0001212, GO:0001213, GO:0001211, GO:0001205 DNA-binding transcription activator activity, RNA polymerase II-specific; • GO:0001200, GO:0001133, GO:0001201 DNA-binding transcription factor activity, RNA polymerase II-specific;
Ćelijska komponenta	• jedro; • nukleoplazma;
Biološki proces	• 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; • Regulacija ekspresije gena; • positive regulation of neuron differentiation; • brainstem development; • inner ear development; • cell development; • GO:0009373 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; • GO:0003257, GO:0010735, GO:1901228, GO:1900622, GO:1904488 positive regulation of transcription by RNA polymerase II; • transcription by RNA polymerase II; • positive regulation of cold-induced thermogenesis; • nervous system development;
	Izvori:Amigo / QuickGO
Ortolozi
	8929
	18935
	ENSG00000109132
	ENSMUSG00000012520
	Q99453
	O35690
	NM_003924
	NM_008888
	NP_003915
	NP_032914
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

Upareni homeoboks 2b (PHOX2B), znan i kao neuroblastom Phox (NBPhox), jest protein koji je kod ljudi kodiran genom PHOX2B sa hromosoma 4.^[5]

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 314 aminokiselina, а molekulska težina 31.621 Da.^[6]

C: Cistein

D: Asparaginska kiselina

E: Glutaminska kiselina

F: Fenilalanin

G: Glicin

H: Histidin

I: Izoleucin

K: Lizin

L: Leucin

M: Metionin

N: Asparagin

P: Prolin

Q: Glutamin

R: Arginin

S: Serin

T: Treonin

V: Valin

W: Triptofan

Y: Tirozin

10	20	30	40	50
MYKMEYSYLN	SSAYESCMAG	MDTSSLASAY	ADFSSCSQAS	GFQYNPIRTT
FGATSGCPSL	TPGSCSLGTL	RDHQSSPYAA	VPYKLFTDHG	GLNEKRKQRR
IRTTFTSAQL	KELERVFAET	HYPDIYTREE	LALKIDLTEA	RVQVWFQNRR
AKFRKQERAA	AAAAAAAKNG	SSGKKSDSSR	DDESKEAKST	DPDSTGGPGP
NPNPTPSCGA	NGGGGGGPSP	AGAPGAAGPG	GPGGEPGKGG	AAAAAAAAAA
AAAAAAAAAA	GGLAAAGGPG	QGWAPGPGPI	TSIPDSLGGP	FASVLSSLQR
PNGAKAALVK	SSMF

Funkcija

Ovaj gen kodira za homeodomenski faktor transkripcije. Eksprimira se isključivo u nervnom sistemu, u većini neurona koji kontrolišu unutrašnje organe (kardiovaskularni, probavni i respiratorni sistem). Potreban je i za njihovu diferencijaciju.

Imunohistohemija

Neophodan za diferencijaciju i preživljavanje simpatičkih neurona i hromafinskih ćelija, faktor transkripcije PHOX2B je visoko specifičan za periferni autonomni nervni sistem. Neuroblasti su izvedeni iz simpatonadbubrežne loze ćelija nervog grebena i stoga zahtevaju i konstitutivno eksprimiraju PHOX2B. Pokazalo se da je imunohistohemijsko bojenje PHOX2-a, kao marker derivacije nervnog grebena, osjetljiv i specifičan za nediferencirani neuroblastom, omogućavajući identifikaciju gdje ga drugi markeri ne prepoznaju među različitim malim okruglim plavim ćelijama djetinjstvenih tumora.^[7]^[8]^[9]^[10]

Dijagnostička korist bojenja PHOX2B-a proteže se na kasnije faze diferencijacije. Njegova snaga i specifičnost mogu otkriti mala žarišta neuroblastnih tumorskih metastataza u koštanoj srži, što je ključna identifikacija za određivanje stadija bolesti. Bojenje PHOX2B također prevazilazi česte prepreke otkrivanju neuroblastoma u uzorcima nakon tretmana, koji često pokazuju gustu fibrozu, istaknute upalne infiltrate i/ili difuznu kalcifikaciju.^[11]

Klinički značaj

Mutacije u ljudskom PHOX2B uzrokuju rijetku bolest visceralnog nervnog sistema (disautonomiju): kongenitalni centralni hipoventilacijski sindrom (povezan sa respiratornim zastojima tokom spavanja i, povremeno, budnosti), Hirschsprungovu bolest (parcijalna ageneza vegetativnog nervnog sistema), ROHHAD i tumore simpatičkih ganglija.

Kod većine ljudi, egzon 3 datog gena sadrži sekvencu od 20 polialaninskih ponavljanja. Povećanje broja ponavljanja povezano je s kongenitalnim centralnim hipoventilacijskim sindromom. Mogu postojati i druge patogene mutacije dalje duž gena.

Reference

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000109132 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000012520 - Ensembl, maj 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".
^ "UniProt, Q99453" (jezik: engleski). Pristupljeno 30. 10. 2021.
^ Bielle, Franck; Fréneaux, Paul; Jeanne-Pasquier, Corinne; Maran-Gonzalez, Aurélie; Rousseau, Audrey; Lamant, Laurence; Paris, Régine; Pierron, Gaëlle; Nicolas, André Victor; Sastre-Garau, Xavier; Delattre, Olivier; Bourdeaut, Franck; Peuchmaur, Michel (2012). "PHOX2B Immunolabeling". The American Journal of Surgical Pathology. 36 (8): 1141–1149. doi:10.1097/PAS.0b013e31825a6895. PMID 22790854. S2CID 25924210.
^ 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. S2CID 19123236.
^ 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. S2CID 3302863.
^ Hata et al. (2015).

Dopunska literatura

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. doi:10.1038/ajg.2008.65. PMID 19262523. 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. doi:10.1203/01.PDR.0000166755.29277.C4. 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. doi:10.1016/j.jpedsurg.2008.12.009. 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. doi:10.1111/j.1651-2227.2008.01039.x. PMID 18798833. 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. doi:10.1111/j.1471-4159.2009.06260.x. 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. doi:10.1186/1471-2164-10-8. PMC 2630312. 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. doi:10.1097/PDM.0b013e3181eb92ff. PMID 21051998. 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. doi:10.1016/j.humpath.2009.08.020. PMID 20004937.
Janoueix-Lerosey I, Schleiermacher G, Delattre O (2010). "Molecular pathogenesis of peripheral neuroblastic tumors". Oncogene. 29 (11): 1566–79. doi:10.1038/onc.2009.518. 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. doi:10.3892/ijo_00000086. 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. doi:10.1055/s-0029-1220941. PMID 19707990.
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. doi:10.1038/jhg.2009.109. 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. doi:10.1378/chest.08-1664. 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. doi:10.1002/humu.20929. PMID 19191321. 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. doi:10.1002/humu.20923. PMID 19058226. 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. doi:10.1523/JNEUROSCI.2623-09.2009. PMC 6665996. 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. doi:10.1097/MPH.0b013e3181772141. PMID 19011468. S2CID 32426671.
Rudzinski E, Kapur RP (2010). "PHOX2B immunolocalization of the candidate human retrotrapezoid nucleus". Pediatr. Dev. Pathol. 13 (4): 291–9. doi:10.2350/09-07-0682-OA.1. PMID 19888871. 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. doi:10.1164/rccm.201002-0192OC. PMC 2970865. 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. doi:10.1111/j.1469-1809.2010.00606.x. PMC 2955808. PMID 20846217.

Vanjski linkovi

GeneReviews/NCBI/NIH/UW entry on Congenital Central Hypoventilation Syndrome
Phox2b protein na US National Library of Medicine Medical Subject Headings (MeSH)

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000109132 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000012520 - Ensembl, maj 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.

[entrez-5] "Entrez Gene: paired-like homeobox 2b".

[UniProt-6] "UniProt, Q99453" (jezik: engleski). Pristupljeno 30. 10. 2021.

[7] Bielle, Franck; Fréneaux, Paul; Jeanne-Pasquier, Corinne; Maran-Gonzalez, Aurélie; Rousseau, Audrey; Lamant, Laurence; Paris, Régine; Pierron, Gaëlle; Nicolas, André Victor; Sastre-Garau, Xavier; Delattre, Olivier; Bourdeaut, Franck; Peuchmaur, Michel (2012). "PHOX2B Immunolabeling". The American Journal of Surgical Pathology. 36 (8): 1141–1149. doi:10.1097/PAS.0b013e31825a6895. PMID 22790854. S2CID 25924210.

[8] 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.

[9] 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. S2CID 19123236.

[10] 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. S2CID 3302863.

[11] Hata et al. (2015).

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