title: Mosaic inv dup(8p) marker chromosome with stable neocentromere suggests neocentromerization is a post-zygotic event.
abstract: Marker chromosomes containing active human neocentromeres have been described in individuals where the chromosomes are non-mosaic, suggesting that they are mitotically stable, but also in individuals where there is mosaicism, raising the possibility of neocentromere instability. We report two independently ascertained individuals who are mosaic for a supernumerary marker chromosome, shown by reverse chromosome painting to have an 8p origin, resulting in mosaicism for tetrasomy 8p23.1-->pter in the patient. The markers have a primary constriction but show no detectable centromeric alpha-satellite DNA. The marker in Patient 1 demonstrated no centromere protein CENP-B binding, but associated with nine different functionally critical centromere proteins. Investigation of peripheral blood lymphocytes from this patient on five separate occasions over a 13-year period showed 23-46% mosaicism for the marker chromosome with no decrease in incidence. In vitro investigation of primary and secondary sub-clones of a lymphoblast cell line derived from the patient demonstrated 100% stability of the marker chromosome indicating that neocentromere instability is unlikely to be responsible for the mosaicism in the patient. This and other available data support a general model of neocentromerization as a post-zygotic event, irrespective of whether the supernumerary chromosome fragment has arisen during meiosis or post-fertilization at mitosis.
authors.affiliation: Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Australia.
authors.forename: L
authors.initials: L
authors.lastname: Voullaire
authors.forename: R
authors.initials: R
authors.lastname: Saffery
authors.forename: E
authors.initials: E
authors.lastname: Earle
authors.forename: D V
authors.initials: DV
authors.lastname: Irvine
authors.forename: H
authors.initials: H
authors.lastname: Slater
authors.forename: S
authors.initials: S
authors.lastname: Dale
authors.forename: D
authors.initials: D
authors.lastname: du Sart
authors.forename: T
authors.initials: T
authors.lastname: Fleming
authors.forename: K H
authors.initials: KH
authors.lastname: Choo
mesh_terms: D000293:Adolescent; D001324:Autoantigens; D002503:Centromere / Q000235:genetics*; D000076247:Centromere Protein A; D051936:Centromere Protein B; D002648:Child; D002675:Child, Preschool; D002868:Chromosomal Proteins, Non-Histone / Q000032:analysis / Q000235:genetics; D007446:Chromosome Inversion; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D004268:DNA-Binding Proteins; D005455:Fluorescent Antibody Technique; D020440:Gene Duplication; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D008297:Male; D008957:Models, Genetic; D009030:Mosaicism; D011494:Protein Kinases / Q000032:analysis / Q000235:genetics; D017346:Protein Serine-Threonine Kinases; D015053:Zygote / Q000254:growth & development / Q000378:metabolism
chemical_list: D001324:Autoantigens; C497926:CENPB protein, human; D000076247:Centromere Protein A; D051936:Centromere Protein B; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D011494:Protein Kinases; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases