The PHOX2B gene provides instructions for making a protein that is important during development before birth. The PHOX2B protein helps support the formation of nerve cells (neurons) and regulates the process by which the neurons mature to carry out specific functions (differentiation). During neuron development, 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.
Health Conditions Related to Genetic Changes
Several mutations in the PHOX2B gene have been identified in people with neuroblastoma, a type of cancerous tumor composed of immature neurons (neuroblasts). Neuroblastoma and other cancers occur when a buildup of genetic mutations 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 supporting neuron differentiation, which results in an excess of immature neurons and leads to neuroblastoma.
Some people with PHOX2B gene mutations have both neuroblastoma and Hirschsprung disease. PHOX2B gene variations affect the autonomic nervous system and tissues that grow from the neural crest, resulting in an increased risk of developing both of these disorders.More About This Health Condition
Congenital central hypoventilation syndrome
More than 75 mutations in the PHOX2B gene have been found to cause congenital central hypoventilation syndrome (CCHS). This condition is characterized by shallow breathing (hypoventilation), especially during sleep, that typically begins in infancy. Affected individuals often have other problems involving the autonomic nervous system, including difficulty regulating heart rate, blood pressure, and body temperature. Some people with CCHS also have abnormalities in the nerves that control the digestive tract (Hirschsprung disease), resulting in severe constipation, intestinal blockage, and enlargement of the colon.
Most PHOX2B gene mutations that cause CCHS add extra alanines to the second polyalanine tract in the PHOX2B protein. This type of mutation is called a polyalanine repeat expansion. The mutations that cause CCHS typically increase the number of alanines from 20 to 25 or more. Other types of PHOX2B gene mutations have been identified in 8 to 10 percent of individuals with this disorder.
PHOX2B gene mutations that cause CCHS are believed to interfere with the PHOX2B protein's role in supporting neuron formation and differentiation, especially in the autonomic nervous system. As a result, bodily functions that are controlled by this system, including regulation of breathing, heart rate, blood pressure, and body temperature, are inconsistent in CCHS.More About This Health Condition
Other Names for This Gene
- neuroblastoma paired-type homeobox protein
- neuroblastoma Phox
- paired like homeobox 2b
- paired mesoderm homeobox 2b
- paired-like homeobox 2b
- PHOX2B homeodomain protein
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
- 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. Citation on PubMed
- Di Lascio S, Benfante R, Di Zanni E, Cardani S, Adamo A, Fornasari D, Ceccherini I, Bachetti T. Structural and functional differences in PHOX2B frameshift mutations underlie isolated or syndromic congenital central hypoventilation syndrome. Hum Mutat. 2018 Feb;39(2):219-236. doi: 10.1002/humu.23365. Epub 2017 Nov 21. Citation on PubMed or Free article on PubMed Central
- 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. Citation on PubMed
- Katwa U, D'Gama AM, Qualls AE, Donovan LM, Heffernan J, Shi J, Agrawal PB. Atypical presentations associated with non-polyalanine repeat PHOX2B mutations. Am J Med Genet A. 2018 Jul;176(7):1627-1631. doi: 10.1002/ajmg.a.38720. Epub 2018 Apr 28. Citation on PubMed or Free article on PubMed Central
- 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. Citation on PubMed
- 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. Citation on PubMed
- 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. Citation on PubMed
- Sasaki A, Kishikawa Y, Imaji R, Fukushima Y, Nakamura Y, Nishimura Y, Yamada M, Mino Y, Mitsui T, Hayasaka K. Novel PHOX2B mutations in congenital central hypoventilation syndrome. Pediatr Int. 2019 Apr;61(4):393-396. doi: 10.1111/ped.13812. Epub 2019 Apr 17. Citation on PubMed
- 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. Citation on PubMed
- Weese-Mayer DE, Rand CM, Khaytin I, Slattery SM, Yap KL, Marazita ML, Berry-Kravis EM. Congenital Central Hypoventilation Syndrome. 2004 Jan 28 [updated 2021 Jan 28]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Mirzaa GM, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from http://www.ncbi.nlm.nih.gov/books/NBK1427/ Citation on PubMed