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J Hum Genet. 2010 Jan;55(1):4-7. doi: 10.1038/jhg.2009.109. Epub 2009 Oct 30.

Polyalanine expansion of PHOX2B in congenital central hypoventilation syndrome: rs17884724:A>C is associated with 7-alanine expansion.

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  • 1Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan.


With congenital central hypoventilation syndrome (CCHS), most patients have a de novo 5-13 polyalanine expansion mutation in PHOX2B. We reported previously that de novo polyalanine expansion mutations were of paternal origin and were derived from unequal sister chromatid exchange during spermatogenesis in six and four informative families, respectively. In this study, we analyzed the relationship between haplotypes and de novo polyalanine expansion in PHOX2B and found that haplotypes carrying rs17884724:A>C were detected frequently in 7-alanine expanded (27-alanine) mutant alleles, which are the most prevalent mutations in CCHS. The allele with rs17884724:A>C made fewer nucleotide mismatches in the misalignment at crossing-over than the allele without rs17884724:A>C. The high frequency of rs17884724:A>C in 7-alanine expansion (27-alanine) mutations also supported the unequal crossover mechanism for polyalanine expansion. We also confirmed the paternal origin of de novo polyalanine expansion mutation and unequal sister chromatid exchange association in three more patients. In spite of paternal bias, the paternal age effect on CCHS incidence was not observed. De novo polyalanine expansion mutations are mainly derived from unequal sister chromatid exchange during spermatogenesis because of replication and/or repair systems that are specific for spermatogenesis.

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