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Uptodate Reference Title
PHOX2B gene and molecular mechanisms of congenital central hypoventilation syndrome
PHOX2B gene and molecular mechanisms of congenital central hypoventilation syndrome
Congenital central hypoventilation syndrome (CCHS) is caused by heterozygous mutations in PHOX2B (paired-like homeobox 2B) gene, located on chromosome 4p12. Panel A: Most cases of CCHS are caused by expansions of a 20-polyalanine tract on exon 3 of the PHOX2B gene. Heterozygous expansions to 25, 26 or 27 polyalanines are most frequent. Four different codons (GCA, GCC, GCG, and GCT), as shown by different colors, code for alanine. The blue segments on exons two and three represent the homeodomain. Panel B: When the sequence of codons in the polyalanine tracts from the mother and father are different, it is possible to determine the parental chromosome from which a de novo mutation is derived. In the example shown, note that it would only be possible for the duplicated seven codons found in the affected child to have been derived from a paternal chromosome.[1] Additional upstream and downstream testing for polymorphisms has likewise confirmed that most PARM mutations in the PHOX2B gene are derived from paternal chromosomes.[2] The mechanism is thought to be unequal sister chromatid exchange during spermatogenesis.
CCHS: congenital central hypoventilation syndrome; PARM: polyalanine repeat expansion mutation.
Adapted from the following sources:
Arai H, Otagiri T, Sasaki A et al. De novo polyalanine expansion of PHOX2B in congenital central hypoventilation syndrome: unequal sister chromatid exchange during paternal gametogenesis. J Hum Genet 2007; 52:921.
Arai H, Otagiri T, Sasaki A et al. Polyalanine expansion of PHOX2B in congenital central hypoventilation syndrome: rs17884724:A>C is associated with 7-alanine expansion. J Hum Genet 2010; 55:4.
Weese-Mayer DE, Berry-Kravis EM, Ceccherini I, et al. An official ATS clinical policy statement: Congenital central hypoventilation syndrome: genetic basis, diagnosis, and management. Am J Respir Crit Care Med 2010; 181:626
