Matsuura Shinya, Matsumoto Yoshiyuki, Morishima Ken-ichi, Izumi Hideki, Matsumoto Hiroshi, Ito Emi, Tsutsui Keisuke, Kobayashi Junya, Tauchi Hiroshi, Kajiwara Yoshinori, Hama Seiji, Kurisu Kaoru, Tahara Hidetoshi, Oshimura Mitsuo, Komatsu Kenshi, Ikeuchi Tatsuro, Kajii Tadashi
Department of Radiation Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
Am J Med Genet A. 2006 Feb 15;140(4):358-67. doi: 10.1002/ajmg.a.31069.
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.
伴有嵌合型异倍体（MVA）的易患癌症的早发性染色单体分离综合征（PCS综合征）是一种罕见的常染色体隐性疾病，其特征为生长发育迟缓、小头畸形、儿童期癌症、所有染色体的早发性染色单体分离以及各种三体和单体的嵌合现象。最近在8个MVA综合征（可能与PCS综合征相同）家庭中的5个家庭中报道了双等位基因BUB1B突变。我们在此描述了对7个患有PCS综合征的日本家庭进行的BUB1B（编码BubR1）分子分析。在所有研究的7个家庭中均发现了单等位基因BUB1B突变：4个家庭中存在单碱基缺失（1833delT）；每个有1个家庭分别存在剪接位点突变、无义突变和错义突变。来自具有1833delT突变和剪接位点突变患者的转录本显著减少，可能是由于无义介导的mRNA降解所致。在所研究的7个家庭的第二个等位基因中未发现突变，但BUB1B的RT-PCR和BubR1的蛋白质印迹分析表明其转录本有适度减少。两名患者细胞中的BubR1显示蛋白质表达降低且动粒定位减少。后期促进复合体的特异性激活剂p55cdc的表达水平正常，但其动粒关联被消除。通过微细胞介导将15号染色体（包含BUB1B）转移到细胞中可恢复正常的BubR1水平、p55cdc的动粒定位以及对秋水仙酰胺治疗的正常反应。这些发现表明BubR1参与了p55cdc介导的有丝分裂检查点信号传导，并提示BubR1表达（或活性）降低>50%与PCS综合征有关。
