title: Monoallelic BUB1B mutations and defective mitotic-spindle checkpoint in seven families with premature chromatid separation (PCS) syndrome.
abstract: Cancer-prone syndrome of premature chromatid separation (PCS syndrome) with mosaic variegated aneuploidy (MVA) is a rare autosomal recessive disorder characterized by growth retardation, microcephaly, childhood cancer, premature chromatid separation of all chromosomes, and mosaicism for various trisomies and monosomies. Biallelic BUB1B mutations were recently reported in five of eight families with MVA syndrome (probably identical to the PCS syndrome). We here describe molecular analysis of BUB1B (encoding BubR1) in seven Japanese families with the PCS syndrome. Monoallelic BUB1B mutations were found in all seven families studied: a single-base deletion (1833delT) in four families; and a splice site mutation, a nonsense mutation, and a missense mutation in one family each. Transcripts derived from the patients with the 1833delT mutation and the splice site mutation were significantly reduced, probably due to nonsense-mediated mRNA decay. No mutation was found in the second alleles in the seven families studied, but RT-PCR of BUB1B and Western blot analysis of BubR1 indicated a modest decrease of their transcripts. BubR1 in the cells from two patients showed both reduced protein expression and diminished kinetochore localization. Their expression level of p55cdc, a specific activator of anaphase-promoting complex, was normal but its kinetochore association was abolished. Microcell-mediated transfer of chromosome 15 (containing BUB1B) into the cells restored normal BubR1 levels, kinetochore localization of p55cdc, and the normal responses to colcemid treatment. These findings indicate the involvement of BubR1 in p55cdc-mediated mitotic checkpoint signaling, and suggest that >50% decrease in expression (or activity) of BubR1 is involved in the PCS syndrome.
authors.affiliation: Department of Radiation Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan. shinya@hiroshima-u.ac.jp
authors.forename: Shinya
authors.initials: S
authors.lastname: Matsuura
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Morishima
authors.forename: Hideki
authors.initials: H
authors.lastname: Izumi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsumoto
authors.forename: Emi
authors.initials: E
authors.lastname: Ito
authors.forename: Keisuke
authors.initials: K
authors.lastname: Tsutsui
authors.forename: Junya
authors.initials: J
authors.lastname: Kobayashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tauchi
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Kajiwara
authors.forename: Seiji
authors.initials: S
authors.lastname: Hama
authors.forename: Kaoru
authors.initials: K
authors.lastname: Kurisu
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Tahara
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Oshimura
authors.forename: Kenshi
authors.initials: K
authors.lastname: Komatsu
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Ikeuchi
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kajii
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D000483:Alleles; D000595:Amino Acid Sequence; D015153:Blotting, Western; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D002842:Chromatids / Q000235:genetics / Q000473:pathology*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007223:Infant; D018386:Kinetochores / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D009030:Mosaicism; D009154:Mutation / Q000235:genetics*; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D008941:Spindle Apparatus / Q000473:pathology*; D013577:Syndrome
chemical_list: D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins; C577488:CDC20 protein, human; D011494:Protein Kinases; C584277:BUB1 protein, human; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases