The DNA-associated protein encoded by this gene is a member of the paired family of homeobox proteins localized to the nucleus. The protein functions as a transcription factor involved in the development of several major noradrenergic neuron populations and the determination of neurotransmitter phenotype. The gene product is linked to enhancement of second messenger-mediated activation of the dopamine beta-hydroylase, c-fos promoters and several enhancers, including cyclic amp-response element and serum-response element. [provided by RefSeq]
Somatic PHOX2b mutations have been observed almost exclusively in CNS tumors. They are deletions, insertions or substitutions. There are no mutation hot spots.
Defects in PHOX2B are a cause of congenital central hypoventilation syndrome (CCHS); also known as congenital failure of autonomic control or Ondine curse. Most mutations consist of 5-10 alanine expansions in the poly-Ala region from amino acids 241-260. CCHS is a rare disorder characterized by abnormal control of respiration in the absence of neuromuscular or lung disease, or an identifiable brain stem lesion. A deficiency in autonomic control of respiration results in inadequate or negligible ventilatory and arousal responses to hypercapnia and hypoxemia. CCHS is frequently complicated with neurocristopathies such as Hirschsprung disease that occurs in about 16% of CCHS cases.
Defects in PHOX2B are the cause of susceptibility to neuroblastoma type 2 (NBLST2). A common neoplasm of early childhood arising from embryonic cells that form the primitive neural crest and give rise to the adrenal medulla and the sympathetic nervous system.
References (open access):
PHOX2B-mediated regulation of ALK expression: in vitro identification of a functional relationship between two genes involved in neuroblastoma. Bachetti T, Di Paolo D, Di Lascio S, Mirisola V, Brignole C, Bellotti M, Caffa I, Ferraris C, Fiore M, Fornasari D, Chiarle R, Borghini S, Pfeffer U, Ponzoni M, Ceccherini I, Perri P. PLoS One. 2010 Oct 1;5(10).
PHOX2B germline and somatic mutations in late-onset central hypoventilation syndrome. Trochet D, de Pontual L, Straus C, Gozal D, Trang H, Landrieu P, Munnich A, Lyonnet S, Gaultier C, Amiel J. Am J Respir Crit Care Med. 2008 Apr 15;177(8):906-11.