title: De novo polyalanine expansion of PHOX2B in congenital central hypoventilation syndrome: unequal sister chromatid exchange during paternal gametogenesis.
abstract: The expansion of polyalanine repeats is known to cause at least nine disorders, including congenital central hypoventilation syndrome (CCHS). Unequal crossover has been speculated as the expanding mechanism, in contrast to strand slippage in polyglutamine expansion disorders. We carried out segregation analysis of PHOX2B in 13 de novo families with CCHS and found that 6 families were informative regarding a parental origin of polyalanine expansion, with all 6 mutants being of paternal origin. Four of them were also informative regarding a chromosomal event and their mutants were derived from unequal sister chromatid exchange. It is probable that de novo expansion of polyalanine repeats in CCHS results mainly from unequal sister chromatid exchange during spermatogenesis due to the secondary DNA structure of imperfect trinucleotide repeats encoding polyalanine tracts.
authors.affiliation: Department of Pediatrics, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Arai
authors.affiliation: Department of Pediatrics, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan.
authors.forename: Tesshu
authors.initials: T
authors.lastname: Otagiri
authors.affiliation: Department of Pediatrics, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Sasaki
authors.affiliation: Department of Pediatrics, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan.
authors.forename: Taeko
authors.initials: T
authors.lastname: Hashimoto
authors.affiliation: Department of Legal Medicine, Yamagata University School of Medicine, Yamagata, 990-9585, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Umetsu
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.
authors.forename: Katsushi
authors.initials: K
authors.lastname: Tokunaga
authors.affiliation: Department of Pediatrics, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan. hayasaka@med.id.yamagata-u.ac.jp.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Hayasaka
mesh_terms: D002874:Chromosome Mapping; D005718:Gametogenesis; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007040:Hypoventilation / Q000151:congenital*; D010455:Peptides / Q000235:genetics*; D012854:Sister Chromatid Exchange; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D018398:Homeodomain Proteins; C109220:NBPhox protein; D010455:Peptides; D014157:Transcription Factors; C019529:polyalanine