title: Inheritance of polyalanine expansion mutation of PHOX2B in congenital central hypoventilation syndrome.
abstract: Congenital central hypoventilation syndrome (CCHS; MIM 209880) is caused mostly by dominant alanine expansion (most prevalent is 7-alanine expansion) mutations in PHOX2B. More than 90% of the alanine expansion mutations had been considered to be de novo due to unequal crossover during gametogenesis. However, a recent report stated that 25% of patients inherited the alanine-expanded allele from their parents with somatic mosaicism or constitutive mutation. We studied inheritance in 45 unrelated families, and found that one patient (2%) inherited 5-alanine expansion mutation from a parent with late-onset central hypoventilation syndrome and nine patients (20%) inherited 5- to 7-alanine expansion mutation from apparently asymptomatic parents with somatic mosaicism. Analysis using a sensitive method would be recommended to all parents of CCHS proband due to high incidence of somatic mosaicism. The absence of an alanine-contracted allele (expected counterpart allele in unequal crossover) and the highest prevalence of 6-alanine expansion mutation in somatic mosaicism suggest that the somatic mosaicism is likely caused by a mechanism other than an unequal crossover, such as a replication mechanism.
authors.affiliation: Department of Pediatrics, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Meguro
authors.forename: Yuki
authors.initials: Y
authors.lastname: Yoshida
authors.forename: Makiko
authors.initials: M
authors.lastname: Hayashi
authors.forename: Kentaro
authors.initials: K
authors.lastname: Toyota
authors.forename: Tesshu
authors.initials: T
authors.lastname: Otagiri
authors.forename: Narutaka
authors.initials: N
authors.lastname: Mochizuki
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Kishikawa
authors.forename: Ayako
authors.initials: A
authors.lastname: Sasaki
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Hayasaka
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D005190:Family; D005260:Female; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007040:Hypoventilation / Q000151:congenital* / Q000235:genetics; D008297:Male; D009030:Mosaicism; D009154:Mutation / Q000235:genetics*; D010455:Peptides / Q000235:genetics*; D020182:Sleep Apnea, Central / Q000235:genetics*
chemical_list: D018398:Homeodomain Proteins; C491061:PHOX2A protein, human; D010455:Peptides; C019529:polyalanine