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Genetics Home Reference: your guide to understanding genetic conditions
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PHOX2B

Reviewed August 2012

What is the official name of the PHOX2B gene?

The official name of this gene is “paired-like homeobox 2b.”

PHOX2B is the gene's official symbol. The PHOX2B gene is also known by other names, listed below.

What is the normal function of the PHOX2B gene?

The PHOX2B gene provides instructions for making a protein that acts early in development to help promote the formation of nerve cells (neurons) and regulate the process by which the neurons mature to carry out specific functions (differentiation). The protein is active in the neural crest, which is a group of cells in the early embryo that give rise to many tissues and organs. Neural crest cells migrate to form parts of the autonomic nervous system, which controls body functions such as breathing, blood pressure, heart rate, and digestion. Neural crest cells also give rise to many tissues in the face and skull, and other tissue and cell types.

The protein produced from the PHOX2B gene contains two areas where a protein building block (amino acid) called alanine is repeated multiple times. These stretches of alanines are known as polyalanine tracts or poly(A) tracts.

Does the PHOX2B gene share characteristics with other genes?

The PHOX2B gene belongs to a family of genes called homeobox (homeoboxes).

A gene family is a group of genes that share important characteristics. Classifying individual genes into families helps researchers describe how genes are related to each other. For more information, see What are gene families? (http://ghr.nlm.nih.gov/handbook/howgeneswork/genefamilies) in the Handbook.

How are changes in the PHOX2B gene related to health conditions?

congenital central hypoventilation syndrome - caused by mutations in the PHOX2B gene

Most PHOX2B gene mutations that cause congenital central hypoventilation syndrome (CCHS) add extra alanines to the polyalanine tracts in the PHOX2B protein. This type of mutation is called a polyalanine repeat expansion. Other types of PHOX2B gene mutations have been identified in 8 to 10 percent of individuals with this disorder.

Mutations are believed to interfere with the PHOX2B protein's role in promoting neuron formation and differentiation, especially in the autonomic nervous system, resulting in the problems regulating breathing and other autonomic nervous system dysfunction seen in CCHS.

neuroblastoma - increased risk from variations of the PHOX2B gene

Several mutations in the PHOX2B gene have been identified in people with neuroblastoma, a type of cancerous tumor composed of immature nerve cells (neuroblasts). Neuroblastoma and other cancers occur when a buildup of genetic mutations in critical genes—those that control cell proliferation or differentiation—allow cells to grow and divide uncontrollably to form a tumor. In most cases, these genetic changes are acquired during a person's lifetime, called somatic mutations. Somatic mutations are present only in certain cells and are not inherited. Less commonly, gene mutations that increase the risk of developing cancer can be inherited from a parent. Both types of mutation occur in neuroblastoma. Somatic mutations in the PHOX2B gene increase the risk of developing sporadic neuroblastoma, and inherited mutations in the PHOX2B gene increase the risk of developing familial neuroblastoma.

In some people with neuroblastoma, mutations in the PHOX2B gene change a single protein building block (amino acid) in the PHOX2B protein. Other affected individuals may have an addition or deletion of several DNA building blocks (nucleotides) in the PHOX2B gene. Addition or deletion of nucleotides changes the sequence of amino acids in the PHOX2B protein. All of these types of mutations have been found in familial and sporadic neuroblastoma. The mutations are believed to interfere with the PHOX2B protein's role in promoting nerve cell differentiation, which results in an excess of immature nerve cells and leads to neuroblastoma.

other disorders - associated with the PHOX2B gene

Variations in the PHOX2B gene have been associated with increased risk of certain other disorders involving the autonomic nervous system and tissues derived from the neural crest. Particular PHOX2B gene variations have been identified in people who have both congenital central hypoventilation syndrome and a dysfunction of the nerves in the intestine called Hirschsprung disease (this combination of disorders is often called Haddad syndrome). The nerve problems in Hirschsprung disease result in severe constipation, intestinal blockage, and enlargement of the colon in affected individuals. PHOX2B gene mutations have also been identified in people with both neuroblastoma and Hirschsprung disease. In addition, PHOX2B gene variations have been identified in some babies who died of sudden infant death syndrome (SIDS). PHOX2B gene variations likely affect the regulation of neuron differentiation in early development, resulting in an increased risk of these disorders.

Where is the PHOX2B gene located?

Cytogenetic Location: 4p12

Molecular Location on chromosome 4: base pairs 41,744,081 to 41,748,969

The PHOX2B gene is located on the short (p) arm of chromosome 4 at position 12.

The PHOX2B gene is located on the short (p) arm of chromosome 4 at position 12.

More precisely, the PHOX2B gene is located from base pair 41,744,081 to base pair 41,748,969 on chromosome 4.

See How do geneticists indicate the location of a gene? (http://ghr.nlm.nih.gov/handbook/howgeneswork/genelocation) in the Handbook.

Where can I find additional information about PHOX2B?

You and your healthcare professional may find the following resources about PHOX2B helpful.

You may also be interested in these resources, which are designed for genetics professionals and researchers.

What other names do people use for the PHOX2B gene or gene products?

  • NBLST2
  • NBPhox
  • neuroblastoma paired-type homeobox protein
  • neuroblastoma Phox
  • paired mesoderm homeobox 2b
  • Phox2b
  • PHOX2B homeodomain protein
  • PHX2B_HUMAN
  • PMX2B

See How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What glossary definitions help with understanding PHOX2B?

acids ; alanine ; amino acid ; autonomic nervous system ; cancer ; cell ; cell proliferation ; colon ; congenital ; constipation ; deletion ; differentiation ; digestion ; DNA ; embryo ; familial ; gene ; homeobox ; homeodomain ; hypoventilation ; inherited ; intestine ; mesoderm ; mutation ; nerve cell ; nervous system ; neural crest ; neuroblasts ; neuron ; proliferation ; protein ; sporadic ; syndrome ; tissue ; tumor

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://www.ghr.nlm.nih.gov/glossary).

References

  • Antic NA, Malow BA, Lange N, McEvoy RD, Olson AL, Turkington P, Windisch W, Samuels M, Stevens CA, Berry-Kravis EM, Weese-Mayer DE. PHOX2B mutation-confirmed congenital central hypoventilation syndrome: presentation in adulthood. Am J Respir Crit Care Med. 2006 Oct 15;174(8):923-7. Epub 2006 Jul 27. (http://www.ncbi.nlm.nih.gov/pubmed/16873766?dopt=Abstract)
  • Berry-Kravis EM, Zhou L, Rand CM, Weese-Mayer DE. Congenital central hypoventilation syndrome: PHOX2B mutations and phenotype. Am J Respir Crit Care Med. 2006 Nov 15;174(10):1139-44. Epub 2006 Aug 3. (http://www.ncbi.nlm.nih.gov/pubmed/16888290?dopt=Abstract)
  • Gaultier C, Trang H, Dauger S, Gallego J. Pediatric disorders with autonomic dysfunction: what role for PHOX2B? Pediatr Res. 2005 Jul;58(1):1-6. Epub 2005 May 18. Review. (http://www.ncbi.nlm.nih.gov/pubmed/15901893?dopt=Abstract)
  • Gene Review: Congenital Central Hypoventilation Syndrome (http://www.ncbi.nlm.nih.gov/books/NBK1427)
  • Gronli JO, Santucci BA, Leurgans SE, Berry-Kravis EM, Weese-Mayer DE. Congenital central hypoventilation syndrome: PHOX2B genotype determines risk for sudden death. Pediatr Pulmonol. 2008 Jan;43(1):77-86. (http://www.ncbi.nlm.nih.gov/pubmed/18041756?dopt=Abstract)
  • Miao X, Garcia-Barceló MM, So MT, Leon TY, Lau DK, Liu TT, Chan EK, Lan LC, Wong KK, Lui VC, Tam PK. Role of RET and PHOX2B gene polymorphisms in risk of Hirschsprung's disease in Chinese population. Gut. 2007 May;56(5):736. (http://www.ncbi.nlm.nih.gov/pubmed/17440194?dopt=Abstract)
  • NCBI Gene (http://www.ncbi.nlm.nih.gov/gene/8929)
  • Parodi S, Bachetti T, Lantieri F, Di Duca M, Santamaria G, Ottonello G, Matera I, Ravazzolo R, Ceccherini I. Parental origin and somatic mosaicism of PHOX2B mutations in Congenital Central Hypoventilation Syndrome. Hum Mutat. 2008 Jan;29(1):206. (http://www.ncbi.nlm.nih.gov/pubmed/18157832?dopt=Abstract)
  • Raabe EH, Laudenslager M, Winter C, Wasserman N, Cole K, LaQuaglia M, Maris DJ, Mosse YP, Maris JM. Prevalence and functional consequence of PHOX2B mutations in neuroblastoma. Oncogene. 2008 Jan 17;27(4):469-76. Epub 2007 Jul 16. (http://www.ncbi.nlm.nih.gov/pubmed/17637745?dopt=Abstract)
  • Reiff T, Tsarovina K, Majdazari A, Schmidt M, del Pino I, Rohrer H. Neuroblastoma phox2b variants stimulate proliferation and dedifferentiation of immature sympathetic neurons. J Neurosci. 2010 Jan 20;30(3):905-15. doi: 10.1523/JNEUROSCI.5368-09.2010. (http://www.ncbi.nlm.nih.gov/pubmed/20089899?dopt=Abstract)
  • Repetto GM, Corrales RJ, Abara SG, Zhou L, Berry-Kravis EM, Rand CM, Weese-Mayer DE. Later-onset congenital central hypoventilation syndrome due to a heterozygous 24-polyalanine repeat expansion mutation in the PHOX2B gene. Acta Paediatr. 2009 Jan;98(1):192-5. doi: 10.1111/j.1651-2227.2008.01039.x. Epub 2008 Sep 16. (http://www.ncbi.nlm.nih.gov/pubmed/18798833?dopt=Abstract)
  • Trochet D, Hong SJ, Lim JK, Brunet JF, Munnich A, Kim KS, Lyonnet S, Goridis C, Amiel J. Molecular consequences of PHOX2B missense, frameshift and alanine expansion mutations leading to autonomic dysfunction. Hum Mol Genet. 2005 Dec 1;14(23):3697-708. Epub 2005 Oct 25. (http://www.ncbi.nlm.nih.gov/pubmed/16249188?dopt=Abstract)
  • Weese-Mayer DE, Berry-Kravis EM, Ceccherini I, Rand CM. Congenital central hypoventilation syndrome (CCHS) and sudden infant death syndrome (SIDS): kindred disorders of autonomic regulation. Respir Physiol Neurobiol. 2008 Dec 10;164(1-2):38-48. doi: 10.1016/j.resp.2008.05.011. Review. (http://www.ncbi.nlm.nih.gov/pubmed/18579454?dopt=Abstract)
  • Weese-Mayer DE, Berry-Kravis EM, Marazita ML. In pursuit (and discovery) of a genetic basis for congenital central hypoventilation syndrome. Respir Physiol Neurobiol. 2005 Nov 15;149(1-3):73-82. Epub 2005 Jul 28. Review. (http://www.ncbi.nlm.nih.gov/pubmed/16054879?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: August 2012
Published: September 29, 2014