PHOX2B

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.

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.

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 variations have been identified in people with dysfunction of the nerves in the intestine (Hirschsprung disease), resulting in severe constipation, intestinal blockage, and enlargement of the colon. Researchers have also identified PHOX2B variations associated with a hereditary tendency to develop tumors called neuroblastomas in nerve tissue. In addition, PHOX2B variations have been identified in some babies who died of sudden infant death syndrome (SIDS). PHOX2B variations likely affect the regulation of neuron differentiation in early development, resulting in an increased risk of these disorders.