Interphase chromosomal abnormalities and mitotic missegregation of hypomethylated sequences in ICF syndrome cells
Interphase chromosomal abnormalities and mitotic missegregation of hypomethylated sequences in ICF syndrome cells
复制标题
DOI：
10.1007/s00412-005-0343-7
复制
发表时间：
2005-07-01
期刊：
影响因子：
1.6
通讯作者：
Ehrlich, M
中科院分区：
文献类型：
--
作者：
Gisselsson, D;Shao, CB;Ehrlich, M
免疫缺陷、着丝粒区不稳定、面部畸形综合征是一种罕见的常染色体隐性遗传病。通常，它是由DNA甲基转移酶3B基因的突变引起的，这导致在1 qh，16 qh和9 qh的着丝粒异染色质中卫星DNA的甲基化减少。富含卫星II的1 qh和16 qh显示有丝分裂原刺激的ICF淋巴细胞异常的高频率，而这些细胞不容易发生非整倍体。在这里，我们发现，在淋巴母细胞系从4 ICF患者，有增加的共定位的低甲基化1 qh和16 qh序列在间期，异常循环的pericentromeric DNA序列在中期，形成桥梁在后期，染色体1和16片段在末期间期过渡，并在凋亡细胞，微核与染色体1和16材料的过度表达。ICF细胞中后期桥接的另一个来源是染色体之间的随机端粒缔合。我们的研究结果阐明了ICF染色体异常的形成机制，并建议，1 qh-16 qh协会在间期可能会导致有丝分裂分离的障碍，导致微核的形成，有时凋亡。这可以帮助解释为什么特定类型的1 qh和16 qh重排在ICF淋巴细胞中不以高频率存在，尽管不断产生不同的1 qh和16 qh畸变。
The immunodeficiency, centromeric region instability, facial anomalies (ICF) syndrome is a rare autosomal recessive disease. Usually, it is caused by mutations in the DNA methyltransferase 3B gene, which result in decreased methylation of satellite DNA in the juxtacentromeric heterochromatin at 1qh, 16qh, and 9qh. Satellite II-rich 1qh and 16qh display high frequencies of abnormalities in mitogen-stimulated ICF lymphocytes without these cells being prone to aneuploidy. Here we show that in lymphoblastoid cell lines from four ICF patients, there was increased colocalization of the hypomethylated 1qh and 16qh sequences in interphase, abnormal looping of pericentromeric DNA sequences at metaphase, formation of bridges at anaphase, chromosome 1 and 16 fragmentation at the telophase-interphase transition, and, in apoptotic cells, micronuclei with overrepresentation of chromosome 1 and 16 material. Another source of anaphase bridging in the ICF cells was random telomeric associations between chromosomes. Our results elucidate the mechanism of formation of ICF chromosome anomalies and suggest that 1qh-16qh associations in interphase can lead to disturbances of mitotic segregation, resulting in micronucleus formation and sometimes apoptosis. This can help explain why specific types of 1qh and 16qh rearrangements are not present at high frequencies in ICF lymphoid cells despite diverse 1qh and 16qh aberrations continuously being generated.