title: Parental origin and somatic mosaicism of PHOX2B mutations in Congenital Central Hypoventilation Syndrome.
abstract: Heterozygous polyalanine repeat expansions of PHOX2B have been associated with Congenital Central Hypoventilation Syndrome, a rare neurocristopathy characterized by absence of adequate control of respiration during sleep. Here we report a PHOX2B mutational screening in 63 CCHS patients, 58 of whom presenting with poly-A expansions or frameshift, missense and nonsense mutations. To assess a somatic or germline occurrence of poly-A length variations, the relative amounts of mutant and wild type alleles have been quantified in 20 selected CCHS patients presenting with an expansion, and in their parents. Somatic mosaicism was shown in four parents, while no mosaic was found among CCHS patients. Moreover, while co-segregation analysis of the PHOX2B poly-A expansions with selected marker alleles in the same 20 CCHS trios has not demonstrated any parent-of-origin effect of the mutations, it has provided further clues to clarify the molecular mechanism underlying the expansion occurrence. Finally, the segregation of PHOX2B poly-A anomalous tracts within family members has allowed us to exclude tendency of polymorphic variations towards expansion. This strengthens the notion that expanded polyalanine tracts, identified as frequent disease-causing mutations also in other human diseases, are mitotically and meiotically stable.
authors.affiliation: Laboratorio di Genetica Molecolare, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Parodi
authors.forename: Tiziana
authors.initials: T
authors.lastname: Bachetti
authors.forename: Francesca
authors.initials: F
authors.lastname: Lantieri
authors.forename: Marco
authors.initials: M
authors.lastname: Di Duca
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Santamaria
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Ottonello
authors.forename: Ivana
authors.initials: I
authors.lastname: Matera
authors.forename: Roberto
authors.initials: R
authors.lastname: Ravazzolo
authors.forename: Isabella
authors.initials: I
authors.lastname: Ceccherini
mesh_terms: D001483:Base Sequence; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009030:Mosaicism; D009154:Mutation; D010455:Peptides / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D020182:Sleep Apnea, Central / Q000151:congenital* / Q000235:genetics*; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; C109220:NBPhox protein; D010455:Peptides; D014157:Transcription Factors; C019529:polyalanine