人类神经退行性疾病相关的三核苷酸重复DNA序列不稳定性机制研究进展

doi:10.16288/j.yczz.21-182

遗传 ›› 2021, Vol. 43 ›› Issue (9): 835-848.doi: 10.16288/j.yczz.21-182

人类神经退行性疾病相关的三核苷酸重复DNA序列不稳定性机制研究进展

吕柯孬¹, 潘学峰^1,^2,³()

1. 北京理工大学生命学院,北京 100081
2. 河北大学医学院,保定 071030
3. 河北大学化学与环境科学学院,保定 071002

收稿日期:2021-05-24 修回日期:2021-07-25 出版日期:2021-09-20 发布日期:2021-08-05
通讯作者: 潘学峰 E-mail:xuefengpancam@aliyun.com
作者简介:吕柯孬,在读硕士研究生,专业方向：分子生物学。E-mail: 2829435034@qq.com
基金资助:
北京市自然科学基金No(5132014);河北省医学研究计划重点项目资助No(20160051)

Progress on the mechanistic research of the trinucleotide repeat instabilities underlying human neurodegenerative diseases

Kenao Lv¹, Xuefeng Pan^1,^2,³()

1. School of Life Science, Beijing Institute of Technology, Beijing 100081, China
2. School of Medicine, Hebei University, Baoding 071030, China
3. School of Chemistry and Enviromental Science, Hebei University, Baoding 071002, China

Received:2021-05-24 Revised:2021-07-25 Online:2021-09-20 Published:2021-08-05
Contact: Pan Xuefeng E-mail:xuefengpancam@aliyun.com
Supported by:
Supported by Beijing Natural Science Foundation No(5132014);Hebei Medical Research Key Program No(20160051)

摘要/Abstract

摘要：

三核苷酸重复DNA序列扩增或缺失不稳定性与50多种人类神经退行性疾病有关。与疾病相关的三核苷酸重复拷贝数的增加或减少,影响了特定基因的表达,或因之产生具有细胞毒性的RNA和蛋白质已成为相关疾病的共有病理机制。现有的研究表明,疾病相关的三核苷酸重复拷贝数的改变有可能起因于相关三核苷酸重复DNA序列的异常DNA复制、修复、重组以及基因转录。有关人类遗传学研究也提示,发生在疾病相关的三核苷酸重复DNA部位的异常DNA复制、修复、重组或基因转录确有可能在三核苷酸重复DNA不稳定过程中发挥着关键作用。本文根据本课题组的研究经验,综述了近年来有关疾病相关三核苷酸重复不稳定性机制的研究进展,包括碱基突变不稳定、重复单元的扩增和缺失不稳定,以助更好地理解疾病相关三核苷酸重复DNA序列不稳定性的分子机制。

关键词: 三核苷酸重复, 不稳定性扩增, R-环, 非B型DNA二级结构, 神经退行性疾病

Abstract:

The expansion and deletion instabilities shown by some trinucleotide repeated DNA sequences are associated with more than 50 neurodegenerative diseases in humans. The increase or decrease of the trinucleotide repeat units underlying the diseases are not yet clearly explained using any mechanism, but has been found to affect the expression of specific genes, or produces cytotoxic RNA and protein, which has now become a common pathological mechanism of the diseases. The ongoing studies have shown that the changes in the copy numbers of the disease-related trinucleotide repeats may result from abnormal DNA replication, repair, recombination, and gene transcription. Human genetical studies also suggest that abnormal DNA replication, repair, recombination, or gene transcription that occurred in the disease-related trinucleotide repeat DNA sites may play a key role in the trinucleotide repeat DNA instabilities. Based on the research experiences of our research group, this paper reviews the recent research progress on the mechanisms of the disease-associated trinucleotide repeat DNA instabilities including their base mutation instabilities, the amplification and deletion instabilities of the repeat units, to better understand the molecular mechanism of the disease-associated trinucleotide repeats instabilities.

Key words: trinucleotide repeats, expansion instability, RNA: DNA hybrids, non-B DNA secondary structure, neurodegenerative disease

吕柯孬, 潘学峰. 人类神经退行性疾病相关的三核苷酸重复DNA序列不稳定性机制研究进展[J]. 遗传, 2021, 43(9): 835-848.

Kenao Lv, Xuefeng Pan. Progress on the mechanistic research of the trinucleotide repeat instabilities underlying human neurodegenerative diseases[J]. Hereditas(Beijing), 2021, 43(9): 835-848.

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类型	疾病名称	基因	三核苷酸重复DNA序列	基因结构	染色体定位	正常重复数	异常重复数	首次报道时间	参考文献
PolyQ 三核苷酸扩增性疾病	脊髓小脑共济失调 1型	ATXN1	CAG	ORF	6p22.3	6~9	41~83	1993	[16]
	脊髓小脑共济失调 2型	ATXN2	CAG	ORF	12q24.12	14~32	33~200	1996	[17,18]
	脊髓小脑共济失调 3型	ATXN3	CAG	ORF	14q32.12	12~40	55~86	1994	[19]
	脊髓小脑共济失调 6型	CACNA1A	CAG	ORF	19p13.13	4~18	21~33	1997	[20]
	脊髓小脑共济失调 7型	ATXN7	CAG	ORF	3p14.1	7~17	38~120	1997	[21]
	脊髓小脑共济失调 12型	PPP2R2B	CAG	5′UTR	5q32	7~41	>51	1999	[22]
	脊髓小脑共济失调 17型	TBP	CAG	ORF	6q27	25~44	47~63	2001	[23]
	亨廷顿舞蹈病	HTT	CAG	ORF	4p16.3	6~35	36~250	1993	[24]
	脊髓延髓肌萎缩	AR	CAG	ORF	Xq12	9~36	38~62	1991	[25]
非polyQ 三核苷酸扩增性疾病	易碎性X综合征	FMR1	CGG	5′UTR	Xq27.3	6~53	>230	1991	[26,27]
	易碎性X智力低下(马丁-贝尔综合征)	FMR2	CGG	5′UTR	Xq28	6~53	>200	1993	[28]
	弗洛里德共济失调	FXN	GAA	内含子	9q21.11	7~34	>70	1996	[29]
	强直性肌营养不良	DMPK	CTG	3′UTR	19q13.32	5~37	>50	1992	[30]
	脊髓小脑共济失调 8型	SCA8	CTG	ORF	13q21.33	16~37	90~250	1999	[31]

人类神经退行性疾病相关的三核苷酸重复DNA序列不稳定性机制研究进展

Progress on the mechanistic research of the trinucleotide repeat instabilities underlying human neurodegenerative diseases

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非B型 DNA二级结构	Slipped DNA	H-DNA	G4偶联体	含错配发卡结构
示意图
三核苷酸重复DNA序列	所有10种三核苷酸重复	GAA	CGG	CAG
		TTC	AGG	CTG
			TGG	CGG
				CCG

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[6]	牛银波，南亚萍，舒青，张科进，高晓彩，张富昌. 秦巴山区儿童FRAXE脆性位点CGG重复多态性分布及与智力的相关性分析[J]. 遗传, 2006, 28(10): 1219-1223.
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[8]	肖翠英，武辉，潘阿根，张思仲. 强直性肌营养不良症DMPK基因CTG重复序列与Alu±1kb单倍型研究[J]. 遗传, 2000, 22(2): 81-84.
[9]	敬慧娥，张思仲，肖翠英，武辉. 中国羌族人群强直性肌营养不良症基因CTG重复序列多态性研究[J]. 遗传, 1998, 20(4): 7-11.