ICF, an immunodeficiency syndrome: DNA methyltransferase 3B involvement, chromosome anomalies, and gene dysregulation.
ICF, an immunodeficiency syndrome: DNA methyltransferase 3B involvement, chromosome anomalies, and gene dysregulation.
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ICF，一种免疫缺陷综合征：DNA甲基转移酶3B受累，染色体异常和基因失调。
DOI：
10.1080/08916930802024202
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发表时间：
2008-05
期刊：
影响因子：
3.5
通讯作者：
Hanash, Samir M.
中科院分区：
文献类型：
--
作者：
Ehrlich, Melanie;Sanchez, Cecilia;Shao, Chunbo;Nishiyama, Rie;Kehrl, John;Kuick, Rork;Kubota, Takeo;Hanash, Samir M.
关键词：
免疫缺陷、着丝粒区不稳定和面部异常综合征（ICF）是已知由突变的DNA甲基转移酶基因（即DNMT 3B）引起的唯一疾病。这种隐性遗传病的特征是血清免疫球蛋白降低，尽管存在B细胞，在1号和16号染色体的近着丝粒异染色质中，染色质解凝聚，独特的重排和卫星DNA低甲基化。尽管DNMT 3B与组蛋白脱乙酰酶、HP 1、其他DNMT、染色质重塑蛋白、凝聚素和其他核蛋白有特异性关联，但可能是催化活性的部分丧失导致了该疾病。在微阵列实验和实时RT-PCR分析中，我们观察到ICF与对照淋巴母细胞中促凋亡基因和抗凋亡基因的RNA水平存在显著差异。（BCL 2L 10、CASP 1和PTPN 13）;一氧化二氮、一氧化碳、NF-κB和TNF α信号通路基因（PRKCH、GUCY 1A 3、GUCY 1B 3、MAPK 13; HMOX 1和MAP 4K 4）;和转录控制基因（NR 2F 2和SMARCA 2）。这种基因失调可能导致免疫缺陷和ICF的其他症状，并可能导致有限的DNA甲基化的损失，虽然ICF相关的启动子低甲基化没有观察到上述检查的基因。我们建议，卫星2at 1 qh和16 qh的低甲基化可能会引起这种失调的基因表达的转录因子，核结构的变化，或非编码RNA的表达改变隔离的反式效应。
The immunodeficiency, centromeric region instability, and facial anomalies syndrome (ICF) is the only disease known to result from a mutated DNA methyltransferase gene, namely, DNMT3B. Characteristic of this recessive disease are decreases in serum immunoglobulins despite the presence of B cells and, in the juxtacentromeric heterochromatin of chromosomes 1 and 16, chromatin decondensation, distinctive rearrangements, and satellite DNA hypomethylation. Although DNMT3B is involved in specific associations with histone deacetylases, HP1, other DNMTs, chromatin remodelling proteins, condensin, and other nuclear proteins, it is probably the partial loss of catalytic activity that is responsible for the disease. In microarray experiments and real-time RT-PCR assays, we observed significant differences in RNA levels from ICF vs. control lymphoblasts for pro- and anti-apoptotic genes (BCL2L10, CASP1, and PTPN13); nitrous oxide, carbon monoxide, NF-κB, and TNFa signalling pathway genes (PRKCH, GUCY1A3, GUCY1B3, MAPK13; HMOX1, and MAP4K4); and transcription control genes (NR2F2 and SMARCA2). This gene dysregulation could contribute to the immunodeficiency and other symptoms of ICF and might result from the limited losses of DNA methylation although ICF-related promoter hypomethylation was not observed for six of the above examined genes. We propose that hypomethylation of satellite 2at1qh and 16qh might provoke this dysregulation gene expression by trans effects from altered sequestration of transcription factors, changes in nuclear architecture, or expression of noncoding RNAs.
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