Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome

Congenital central hypoventilation syndrome: PHOX2B genotype determines risk for sudden death

“…At day 33, PHOX2B is expressed in terminal rhombomeres 4-8, in the presumptive enteric ganglia, the sympathetic chain ganglia, and the presumptive carotid body at the carotid bifurcation. 6 In PHOX2B-knockout mice the carotid body and autonomic visceral sensory ganglia, including the geniculate, petrosal, and nodose ganglia, fail to form properly and degenerate, and the solitary tract nucleus, their central target which integrates all visceral information including cardiorespiratory regulation, never develops. 25,26 This lack of visceral input may help explain the distinctive lack of flexibility of the cardiovascular system in children with CCHS, thereby increasing their vulnerability to sudden death.…”

“…4,5 Paired-like homeobox (PHOX)2B is the disease-defining gene for CCHS. [6][7][8][9] Individuals with the CCHS phenotype are heterozygous for a polyalanine (PA) repeat expansion mutation in the PHOX2B gene in 92% of cases and non-PA repeat mutations in PHOX2B in 8% of cases. [6][7][8][9][10][11] The 15-39 nucleotide insertions result in expansion of the normal 20 repeat polyalanine tract to 25-33 repeats and genotypes of 20/25 to 20/33.…”

Sensitive Detection of Polyalanine Expansions in PHOX2B by Polymerase Chain Reaction Using Bisulfite-Converted DNA

“…11 In addition to the stable 20-residue repeat, contracted products of 13-and 15-residue repeat were evident, consistent with previous observations. [2][3][4][5] However, no expansions were encountered in both groups. Weese-Mayer and colleagues 13 have reported that no expansions were evident in 97 SIDS cases.…”

“…Hypercapnia and hypoxia caused by apnea are life threatening unless the patient is under intensive clinical care. Amiel and colleagues 2 presented evidence that the paired-like homeobox 2B (PHOX2B) gene is the predominant disease locus in CCHS. The disease exhibits de novo mutations and autosomal dominant inheritance caused by triplet expansions of a stable 20-residue polyalanine repeat encoded in exon 3 of the gene.…”

“…The unusually high GC content interferes with direct polymerase chain reaction (PCR) amplification, except for that of relatively large fragments more than 380 bp. 2,4 Even when PCR does operate, the smaller repeat allele is predominant, allowing the possibility that the other fully expanded allele does not undergo successful amplification. 4,8 To avoid technical difficulties arising from high GC contents, a bisulfite treatment for DNA has been developed for Gand C-containing repeat expansions such as that in fragile X syndrome.…”