De novo polyalanine expansion of PHOX2B in congenital central hypoventilation syndrome: unequal sister chromatid exchange during paternal gametogenesis.
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.
Arai
Hiroko
H
Department of Pediatrics, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan.
Otagiri
Tesshu
T
Department of Pediatrics, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan.
Sasaki
Ayako
A
Department of Pediatrics, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan.
Hashimoto
Taeko
T
Department of Pediatrics, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan.
Umetsu
Kazuo
K
Department of Legal Medicine, Yamagata University School of Medicine, Yamagata, 990-9585, Japan.
Tokunaga
Katsushi
K
Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.
Hayasaka
Kiyoshi
K
Department of Pediatrics, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan. hayasaka@med.id.yamagata-u.ac.jp.
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*
D018398:Homeodomain Proteins; C109220:NBPhox protein; D010455:Peptides; D014157:Transcription Factors; C019529:polyalanine