Nature Genetics:这个基因竟与四种罕见神经退行性疾病都有关

2019-07-24 苏煜静 生物探索

神经退行性疾病一直是医学研究难以攻克的一大疾病,像是阿尔茨海默症、帕金森、癫痫、亨廷顿病等都是我们所熟悉的神经退行性疾病。当然,对于一些罕见的神经退行性疾病科学家也没有放弃。同一种疾病可能是由于不同的基因突变导致的,这就使得许多遗传性疾病治疗变得复杂。如果能够找到其中的共同点,或将为治疗带来新方法。

神经退行性疾病一直是医学研究难以攻克的一大疾病,像是阿尔茨海默症、帕金森、癫痫、亨廷顿病等都是我们所熟悉的神经退行性疾病。当然,对于一些罕见的神经退行性疾病科学家也没有放弃。同一种疾病可能是由于不同的基因突变导致的,这就使得许多遗传性疾病治疗变得复杂。如果能够找到其中的共同点,或将为治疗带来新方法。

近日,日本东京大学的研究人员们在《Nature Genetics》杂志发表论文称,同一个基因在四种不同的罕见神经退行性疾病患者身上均出现重复扩增的现象。DOI:10.1038 / s41588-019-0458-z

这个基因或是罕见病的罪魁祸首

神经元核内包涵体疾病(NIID)是一种罕见的神经退行性疾病。患者表现出认知障碍、运动失控、失去平衡、四肢无力或是吞咽困难等症状。不久前在《American Journal of Human Genetics》上发表的一篇研究中,名古屋大学医学研究生院神经学教授Gen Sobue的研究团队通过对8个家庭13名受NIID影响个体和4个未受影响个体的分析发现,NIID与X染色体上的遗传密码子CGG会重复有关,首次揭示了DNA序列重复与神经退行性疾病之间的关系。

而在由东京大学医学助理教授Hiroyuki Ishiura和他的同事发表的最新研究中,他们进一步调查了四个患有NIID疾病的家族。研究人员对四组家庭成员进行基因检测,依靠短序列读取与智能数据(一种新的“TRhist”程序)分析相结合的方法,生成包含串联重复序列的段读取直方图。经分析发现只有在患者的基因组中出现了CGG重复扩增的现象。

高科技清道夫助力研究分析

在人类46条染色体上搜索CGG重复突变对于传统DNA测序技术而言是相当困难的,此次Ishiura教授所在团队的研究人员设计了一种新方法,借助新一代基因组测序并新开发出一种名为“TRhist”的计算机程序进行智能数据分析。

研究人员对患者和健康人的整个基因组进行了测序,通过TRhist对所有短序列进行排序,并一遍又一遍地搜索由CGG组成的序列。再对比健康人类基因组的标准序列,计算机程序可以将包含CGG重复突变的那些短片段定位到染色体区域。

如此一来,研究人员便能将他们的搜索范围缩小到基因组中的任何地方,在这一染色体区域内只有患者有大量的CGG重复,而健康的人没有。

有了这些信息,研究人员就会知道对哪些染色体区域进行测序,来明确检测这些区域内的基因以及CGG重复突变在这些基因中的具体位置。

CGG重复扩增与其他三种罕见病有关

由于NIID与伴有白质脑病(OPML)的眼咽病、眼咽肌病(OPDM)和眼咽肌营养不良症(OPMD)这三种罕见的神经退行性疾病具有相似的症状和临床检测结果,因此研究人员预测:相同的CGG重复突变可能会导致其他三种罕见的疾病。为了验证这一猜想,Ishiura教授和他的同事也采用了同样的方法来寻找其他相关疾病相关基因的重复扩增。

研究结果表明,CGG基因的重复扩增对另外三种神经系统疾病也有很大影响,并且由于许多重复相似,单一治疗可能针对多种疾病。

结语

Ishiura教授所在团队研究发现所有四种罕见的神经系统疾病都是由CGG相隔较远的、看似无关的基因组区域内重复突变引起的。

其中一种疾病目前只在一个家庭中发现。Ishiura教授说:“我们在十年前就已经开始注意到这个家庭,对我们来说,找到正确的诊断方法是一个长期努力的方向。”

研究人员希望,他们对罕见神经退行性疾病的研究,可能会对其他类型的非编码串联重复突变引起的更常见的疾病有更深的了解。

原始出处:
Hiroyuki Ishiura, Shota Shibata, Jun Yoshimura, et al.Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease,Nature Genetics (2019),22 July 2019

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    2019-09-12 liye789132251
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    2019-08-07 cy0324
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    2020-03-14 canlab
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    2020-04-04 huperzia
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    2019-07-26 syscxl
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    2019-07-24 坚强007

    向挑战病魔的科研人员致敬!

    0

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Lab Invest:泌尿上皮肿瘤细胞中TNFAIP2的表达能够诱导上皮-间质转化和生成铂抗性

基于铂(CDDP)的化疗是许多类型癌症的黄金治疗标准。然而,肿瘤的表型标记在CDDP治疗后总会发生改变,比如发生上皮-间质转化(EMT)和铂抗性。更多的是,癌症细胞在CDDP治疗中获得EMT的机制仍旧不清楚。最近,有研究人员对尿路上皮肿瘤(UC)获得铂抗性前后进行了调查,并发现了一个新的靶标TNFAIP2,该靶标在铂治疗的UC细胞中能够导致EMT和肿瘤浸润。临床上,TNFAIP2表达的上调是3个群

Sci Rep:转移前列腺癌中HOXB13同源异型盒基因能够调控有丝分裂蛋白激酶互作网络

HOXB13是一个同源异型盒转录因子,并且与根治性前列腺切除术后复发有关。虽然HOXB13能够以环境依赖的方式来调控雄激素受体(AR)功能,它在前列腺癌(PC)转移中的关键影响仍旧大部分未知。最近,有研究人员为了鉴定转移性PCs中HOXB13的转录靶标,在人类前列腺肿瘤特异性AR结合位点附近进行了综合的差异化基因表达(DEGs)生物信息学分析。无监督主成分分析(PCA)表明HOXB13靶基因聚焦于

科学家利用机器学习让耐药检测更高效

中国科学院微生物研究所冯婕研究组等针对肺炎链球菌β-内酰胺耐药这一重要临床问题,采用机器学习的方法挖掘耐药相关数据的规律,建立了基因型和表型之间的联系。

Cell Death Dis:IFITM3能够促进前列腺癌细胞的骨转移

晚期阶段前列腺癌(PCa)总是能够诊断出骨转移,并且治疗方法有限。转化生长因子β(TGF-β)能够诱导上皮-间质转化(EMT),并且TGF-β在骨基质中的丰度是重要的生长因素之一,并且有利于骨转移。据报道,TGF-β是骨转移的关键调控因子,但是潜在的机制仍旧不清楚。最近,有研究人员发现干扰素诱导的跨膜蛋白3(IFITM3)通过与Smad4结合激活TGF-β-Smads信号途径,在恶性肿瘤细胞增殖、