Characterization of a de novo balanced t(4;20)(q33;ql2) translocation in a patient with mental retardation.
Characterization of a de novo balanced t(4;20)(q33;ql2) translocation in a patient with mental retardation.
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精神发育迟滞患者的从头平衡 t(4;20)(q33;q12) 易位的表征。
DOI：
10.1002/ajmg.a.33174
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发表时间：
2010
期刊：
影响因子：
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通讯作者：
Wakamatsu N
中科院分区：
文献类型：
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作者：
Yamada K;Fukushi D;Ono T;Kondo Y;Kimura R;Nomura N;Kosaki K;Yamada Y;Mizuno S;Wakamatsu N
CHD 6是一种ATP依赖性染色质重塑酶，被认为是维持和调节染色质结构的关键成分。CHD 6属于最大的亚家族，亚家族III（CHD 6 -9），属于酶的染色体结构域解旋酶DNA（CHD结合蛋白）家族（CHD 1 -9）。我们报告一位平衡易位t（4;20）（q33;q12）的女性患者，表现为严重的智力低下和短趾畸形。我们在CHD 6基因20 q12的内含子27上发现了一个易位断裂点，而4 q33断裂点是基因间断裂点。北方印迹分析显示，患者淋巴母细胞中的CHD 6 mRNA下降至对照细胞的约50%。为了研究CHD亚家族III蛋白减少导致疾病的细胞机制，我们在HeLa细胞中通过RNA干扰敲除CHD 6或CHD 7并分析染色体比对。CHD 6-和CHD 7-敲低细胞均显示中期平板上染色体错配频率增加。此外，在CHD 6和CHD 7单倍体不足的患者中，观察到非整倍体的频率升高，这是流产和精神发育迟滞的主要原因。这些结果表明，CHD 6和CHD 7在有丝分裂过程中的染色质组装中起重要作用，有丝分裂延迟和/或受损的细胞增殖可能与CHD 6或CHD 7突变引起的疾病的发病机制有关。© 2010 Wiley利斯公司
CHD6 is an ATP‐dependent chromatin‐remodeling enzyme, which has been implicated as a crucial component for maintaining and regulating chromatin structure. CHD6 belongs to the largest subfamily, subfamily III (CHD6–9), of the chromodomain helicase DNA (CHD‐binding protein) family of enzymes (CHD1–9). Here we report on a female patient with a balanced translocation t(4;20)(q33;q12) presenting with severe mental retardation and brachydactyly of the toes. We identified the translocation breakpoint in intron 27 ofCHD6at 20q12, while the 4q33 breakpoint was intergenic. Northern blot analysis demonstrated theCHD6mRNA in the patient's lymphoblastoid cells was decreased to ∼50% of the control cells. To investigate the cellular mechanism of diseases resulting from decreased CHD subfamily III proteins, we knocked down CHD6 or CHD7 by RNA interference in HeLa cells and analyzed chromosome alignment. The both CHD6‐ and CHD7‐knockdown cells showed increased frequency of misaligned chromosomes on metaphase plates. Moreover, an elevated frequency of aneuploidy, the major cause of miscarriages and mental retardation, was observed in patients withCHD6andCHD7haploinsufficiency. These results suggest that CHD6 and CHD7 play important roles in chromatin assembly during mitosis and that mitotic delay and/or impaired cell proliferation may be associated with pathogenesis of the diseases caused byCHD6orCHD7mutations. © 2010 Wiley‐Liss, Inc.