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Gene Review

PHOX2B  -  paired-like homeobox 2b

Homo sapiens

Synonyms: NBLST2, NBPhox, Neuroblastoma Phox, PHOX2B homeodomain protein, PMX2B, ...
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Disease relevance of PHOX2B


High impact information on PHOX2B


Chemical compound and disease context of PHOX2B

  • We identified frequent deletion/insertion polymorphisms in the 20-alanine homopolymer stretch of PMX2B, with a modest association between these functional polymorphisms and constant exotropia in schizophrenia (P=0.029) [8].
  • Finally, analysis of cellular toxicity due to polyalanine aggregates has confirmed the occurrence of cell apoptosis consequent to expression of PHOX2B carrying the longest expanded alanine tract and shown that geldanamycin can delay cell progression toward the most advanced apoptotic stages [9].

Biological context of PHOX2B


Anatomical context of PHOX2B

  • We have subsequently shown that heterozygous mutations of PHOX2B may account for several combined or isolated disorders of autonomic nervous-system development--namely, tumors of the sympathetic nervous system (TSNS), such as neuroblastoma and late-onset central hypoventilation syndrome [7].
  • According to the known role of this gene, a transcription factor expressed during autonomic nervous system development, we have tested the transcriptional activity of WT and mutant PHOX2B expression constructs on the regulatory regions of two target genes, DbetaH and PHOX2A [11].
  • Our data provide a possible molecular explanation for the maintenance of PHOX2B expression in developing ganglia, in which initially its expression is triggered by bone morphogenic proteins, but may become independent of external stimuli when it reaches a certain nuclear concentration and sustains its own transcription [12].
  • Because the PHOX2B gene is pivotal in the development of most relays of the autonomic nervous system, including all autonomic neural crest derivatives, it was considered a candidate gene for the above conditions [13].
  • Phox2b is a vertebrate homeodomain transcription factor and a well established intrinsic factor in developing autonomic ganglia, where its expression is triggered by the bone morphogenic proteins secreted by the dorsal aorta [12].

Associations of PHOX2B with chemical compounds

  • Recently, mutations of the PHOX2B gene, especially polyalanine expansions, have been detected in two thirds of patients [10].
  • Moreover, the frameshift due to deletion of a cytosine residue seems to cause sequestration of the corresponding mutant PHOX2B in the nucleolar compartment [11].
  • Moreover, our data suggest that geldanamycin effects on PHOX2B aggregates may be also mediated by the proteasome pathway [9].
  • In addition, we have demonstrated elimination of PHOX2B mutant proteins by the proteasome and autophagy, two cellular mechanisms already been involved in the clearance of proteins containing expanded polyglutamine and polyalanine tracts [9].
  • At the very rostral end of the ventral respiratory column (VRC), Phox2b was present in many VGlut2 (vesicular glutamate transporter 2) mRNA-containing neurons [14].

Other interactions of PHOX2B

  • In conclusion, the polymorphisms of the ARIX gene and PHOX2B gene may be genetic risk factors for the development of congenital superior oblique muscle palsy [15].
  • METHODS: Using polymerase chain reaction amplification and direct sequencing, we screened PHOX2B coding regions and intron/exon boundaries for mutations and polymorphisms in 91 patients with HSCR and 71 ethnically matched controls [3].
  • To assess the genetic mechanisms, we examined the transcription factor genes ARIX (recently identified as a causative gene for syndromic strabismus) and its paralogue, PMX2B [8].
  • A molecular characterization of this rearrangement showed that the 4p13 deletion was 5 Mb in length and included the paired mesoderm homeobox gene (PMX2B) (MIM 603851), a gene expressed in the human embryonic gut and essential for the development of autonomic neural crest derivatives [16].
  • Logistic regression analysis revealed the effect of ASCL1 dominant x PHOX2B additive (P=0.008) as an epistatic gene-gene interaction increasing risk of PD [17].

Analytical, diagnostic and therapeutic context of PHOX2B


  1. The TLX2 homeobox gene is a transcriptional target of PHOX2B in neural-crest-derived cells. Borghini, S., Bachetti, T., Fava, M., Di Duca, M., Cargnin, F., Fornasari, D., Ravazzolo, R., Ceccherini, I. Biochem. J. (2006) [Pubmed]
  2. Molecular consequences of PHOX2B missense, frameshift and alanine expansion mutations leading to autonomic dysfunction. Trochet, D., Hong, S.J., Lim, J.K., Brunet, J.F., Munnich, A., Kim, K.S., Lyonnet, S., Goridis, C., Amiel, J. Hum. Mol. Genet. (2005) [Pubmed]
  3. Association study of PHOX2B as a candidate gene for Hirschsprung's disease. Garcia-Barceló, M., Sham, M.H., Lui, V.C., Chen, B.L., Ott, J., Tam, P.K. Gut (2003) [Pubmed]
  4. Sudden infant death syndrome is not associated with the mutation of PHOX2B gene, a major causative gene of congenital central hypoventilation syndrome. Kijima, K., Sasaki, A., Niki, T., Umetsu, K., Osawa, M., Matoba, R., Hayasaka, K. Tohoku J. Exp. Med. (2004) [Pubmed]
  5. Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome. Amiel, J., Laudier, B., Attié-Bitach, T., Trang, H., de Pontual, L., Gener, B., Trochet, D., Etchevers, H., Ray, P., Simonneau, M., Vekemans, M., Munnich, A., Gaultier, C., Lyonnet, S. Nat. Genet. (2003) [Pubmed]
  6. The homeobox gene Phox2b is essential for the development of autonomic neural crest derivatives. Pattyn, A., Morin, X., Cremer, H., Goridis, C., Brunet, J.F. Nature (1999) [Pubmed]
  7. PHOX2B genotype allows for prediction of tumor risk in congenital central hypoventilation syndrome. Trochet, D., O'Brien, L.M., Gozal, D., Trang, H., Nordenskjöld, A., Laudier, B., Svensson, P.J., Uhrig, S., Cole, T., Niemann, S., Munnich, A., Gaultier, C., Lyonnet, S., Amiel, J. Am. J. Hum. Genet. (2005) [Pubmed]
  8. Association between schizophrenia with ocular misalignment and polyalanine length variation in PMX2B. Toyota, T., Yoshitsugu, K., Ebihara, M., Yamada, K., Ohba, H., Fukasawa, M., Minabe, Y., Nakamura, K., Sekine, Y., Takei, N., Suzuki, K., Itokawa, M., Meerabux, J.M., Iwayama-Shigeno, Y., Tomaru, Y., Shimizu, H., Hattori, E., Mori, N., Yoshikawa, T. Hum. Mol. Genet. (2004) [Pubmed]
  9. Geldanamycin promotes nuclear localisation and clearance of PHOX2B misfolded proteins containing polyalanine expansions. Bachetti, T., Bocca, P., Borghini, S., Matera, I., Prigione, I., Ravazzolo, R., Ceccherini, I. Int. J. Biochem. Cell Biol. (2007) [Pubmed]
  10. Molecular analysis of congenital central hypoventilation syndrome. Sasaki, A., Kanai, M., Kijima, K., Akaba, K., Hashimoto, M., Hasegawa, H., Otaki, S., Koizumi, T., Kusuda, S., Ogawa, Y., Tuchiya, K., Yamamoto, W., Nakamura, T., Hayasaka, K. Hum. Genet. (2003) [Pubmed]
  11. Distinct pathogenetic mechanisms for PHOX2B associated polyalanine expansions and frameshift mutations in congenital central hypoventilation syndrome. Bachetti, T., Matera, I., Borghini, S., Di Duca, M., Ravazzolo, R., Ceccherini, I. Hum. Mol. Genet. (2005) [Pubmed]
  12. PHOX2B regulates its own expression by a transcriptional auto-regulatory mechanism. Cargnin, F., Flora, A., Di Lascio, S., Battaglioli, E., Longhi, R., Clementi, F., Fornasari, D. J. Biol. Chem. (2005) [Pubmed]
  13. Pediatric disorders with autonomic dysfunction: what role for PHOX2B? Gaultier, C., Trang, H., Dauger, S., Gallego, J. Pediatr. Res. (2005) [Pubmed]
  14. Expression of Phox2b by brainstem neurons involved in chemosensory integration in the adult rat. Stornetta, R.L., Moreira, T.S., Takakura, A.C., Kang, B.J., Chang, D.A., West, G.H., Brunet, J.F., Mulkey, D.K., Bayliss, D.A., Guyenet, P.G. J. Neurosci. (2006) [Pubmed]
  15. ARIX and PHOX2B polymorphisms in patients with congenital superior oblique muscle palsy. Jiang, Y., Matsuo, T., Fujiwara, H., Hasebe, S., Ohtsuki, H., Yasuda, T. Acta Med. Okayama (2005) [Pubmed]
  16. PMX2B, a new candidate gene for Hirschsprung's disease. Benailly, H.K., Lapierre, J.M., Laudier, B., Amiel, J., Attié, T., De Blois, M.C., Vekemans, M., Romana, S.P. Clin. Genet. (2003) [Pubmed]
  17. Genetic association analyses of PHOX2B and ASCL1 in neuropsychiatric disorders: evidence for association of ASCL1 with Parkinson's disease. Ide, M., Yamada, K., Toyota, T., Iwayama, Y., Ishitsuka, Y., Minabe, Y., Nakamura, K., Hattori, N., Asada, T., Mizuno, Y., Mori, N., Yoshikawa, T. Hum. Genet. (2005) [Pubmed]
  18. Molecular cloning and characterization of the promoter region of the human Phox2b gene. Jong Hong, S., Chae, H., Kim, K.S. Brain Res. Mol. Brain Res. (2004) [Pubmed]
  19. Characterization of dermatoglyphics in PHOX2B-confirmed congenital central hypoventilation syndrome. Todd, E.S., Scott, N.M., Weese-Mayer, D.E., Weinberg, S.M., Berry-Kravis, E.M., Silvestri, J.M., Kenny, A.S., Hauptman, S.A., Zhou, L., Marazita, M.L. Pediatrics (2006) [Pubmed]
  20. In pursuit (and discovery) of a genetic basis for congenital central hypoventilation syndrome. Weese-Mayer, D.E., Berry-Kravis, E.M., Marazita, M.L. Respiratory physiology & neurobiology. (2005) [Pubmed]
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