Mechanism of cancer susceptibility associated with PCS (premature chromatid separation) genetic trait

1. PCS（过早染色单体分离）综合征是根据我们在7个日本家庭的经验建立的临床实体（omim# 176430），被认为是一种易患癌症的遗传性状，由于有丝分裂纺锤体检查点的损伤，或由于bub1b -内切蛋白（BubR1）的表达减少。PCS细胞的频率是诊断PCS综合征最重要的标志。在PCS性状为纯合子或杂合子的个体中，37℃低渗处理20 min是检测PCS最合适的条件。染色体和DNA多态性标记研究显示，PCS患者的肿瘤发展具有特异性为11号染色体的单系（父系）二体（UPD），提示印迹基因（如父系表达的IGF2）的剂量增加主要参与肿瘤的发展。对7个日本PCS综合征家族进行了BUB1B（编码BubR1蛋白）的分子分析。在所有研究的家族中，发现了单等位基因BUB1B突变：在4个家族中发现了单碱基缺失，在每个家族中发现了剪接位点突变、无义突变和错义突变。对第二个等位基因的单倍型的进一步分析，没有检测到突变，目前正在进行中。从两例PCS患者和来自杂合载体的大量淋巴母细胞样细胞系（LCLs）和成纤维细胞建立并保存。

1. The PCS (premature chromatid separation) syndrome was established as a clinical entity (OMIM#176430) on the basis of our experiences in 7 Japanese families, being recognized to be a cancer-prone genetic trait due to the impairment of mitotic spindle checkpoint, or to the decreased expression of BUB1B-endoding protein (BubR1).2. The frequency of cells in PCS is the most important hallmark for diagnosis of PCS syndrome. Hypotonic treatment of cells at 37℃ for 20 min was found to be most suitable among the conditions tested for the detection of PCS in individuals with the homozygous or heterozygous for the PCS trait.3. Chromosomal and DNA polymorphic marker studies revealed that the tumors developing in PCS patients had uniparental (paternal) disomy (UPD) specifically for chromosome 11, suggesting that the increased dosage of imprinted genes such as paternally expressed IGF2 was primarily involved in tumor development.4. Molecular analysis of BUB1B (encoding BubR1 protein) was performed in 7 Japanese families with PCS syndrome. In all the families studied, monoallelic BUB1B mutations were found : a single-base deletion in 4 families, and a splice site mutation, a nonsence mutation, and a missene mutation in one family each. Further analysis of haplotypes in the secomd alleles, where no mutations were detected, is now in progress.5. Lymphoblastoid cell lines (LCLs) and fibroblasts derived from the two PCS patients and a number of LCLs from heterozygous carriers were established and stored.