Spinocerebellar ataxia type 31 (SCA31).
Spinocerebellar ataxia type 31 (SCA31).
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DOI：
10.1038/s10038-022-01091-4
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发表时间：
2023-03
影响因子：
3.5
通讯作者：
Ishikawa, Kinya
中科院分区：
文献类型：
--
作者：
Ishikawa, Kinya
脊髓小脑型共济失调31型(SCA31)是日本常染色体显性遗传性小脑性共济失调最常见的类型之一。SCA31具有很强的创始人效应，这与该疾病在其他种族中基本不存在的事实相一致。在搜索了2兆碱基(Mb)的整个起始区后，我们最终确定了一个2.5~3.8kb的复杂五核苷酸重复序列，其中包含(TGGAA)n、(TAGAA)n、(TAAAA)n和(TAAAATAGAA)n是区分SCA31个体和正常人的唯一遗传变化。此外，(TGGAA)n被分离为解释致病机理的唯一重复序列，因为在对照日本人中也遇到了其他重复序列。从基因组的角度来看，复杂的五核苷酸重复序列位于两个基因共享的内含子片段中，BEAN1(脑表达，与Nedd4相关)和TK2(胸苷激酶2)以相反的方向转录。虽然TK2普遍表达，但BEAN1只在大脑中转录。因此，复杂的重复序列在大脑中被双向转录为两个独立的非编码重复序列。此外，在SCA31患者的小脑浦肯野细胞核中，发现含有(UGGAA)n的复杂重复序列形成了异常的RNA结构，称为RNA灶。随后在果蝇中过表达(UGGAA)n的研究表明，含有(UGGAA)n的RNA具有长度和表达水平依赖性的毒性，而其毒性可被(UGGAA)n结合蛋白、TDP-43、FUS和hnRNP A2/B1所抑制。通过增强RNA结合蛋白在SCA31中对抗(UGGAA)n毒性的作用来制定治疗策略似乎是合理的。
Spinocerebellar ataxia type 31 (SCA31) is one of the most common forms of autosomal-dominant cerebellar ataxia in Japan. SCA31 has a strong founder effect, which is consistent with the fact that this disease is basically absent in other ethnicities. After searching the entire founder region of a 2-megabase (Mb), we finally identified a 2.5 to 3.8 kb-long complex penta-nucleotide repeat containing (TGGAA)n, (TAGAA)n, (TAAAA)n and (TAAAATAGAA)n as the only genetic change segregating SCA31 individuals from normal people. Furthermore, (TGGAA)n was isolated as the only repeat explaining the pathogenesis because other repeats were encountered in control Japanese. From the genomic point of view, the complex penta-nucleotide repeat lies in an intronic segment shared by two genes, BEAN1 (brain expressed, associated with Nedd4) and TK2 (thymidine kinase 2) transcribed in mutually opposite directions. While TK2 is ubiquitously expressed, BEAN1 is transcribed only in the brain. Thus, the complex repeat is bi-directionally transcribed exclusively in the brain, as two independent non-coding repeats. Furthermore, the complex repeat containing (UGGAA)n was found to form abnormal RNA structures, called RNA foci, in cerebellar Purkinje cell nuclei of SCA31 patients’ brains. Subsequent investigation by over-expressing (UGGAA)n in Drosophila revealed that the RNA containing (UGGAA)n exerts toxicity in a length- and expression level-dependent manner, whereas its toxicity could be dampened by (UGGAA)n-binding proteins, TDP-43, FUS and hnRNP A2/B1. It seems rational to formulate a treatment strategy through enhancing the role of RNA-binding proteins against (UGGAA)n-toxicity in SCA31.
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影响因子：
3.5
作者：
Li, M;Ishikawa, K;Mizusawa, H
通讯作者：
Mizusawa, H
影响因子：
4.4
作者：
Ouyang, Yi;He, Zhiyi;Yuan, Liying
通讯作者：
Yuan, Liying
影响因子：
9.9
作者：
Nagaoka, U;Takashima, M;Mizusawa, H
通讯作者：
Mizusawa, H
DOI：
10.3760/cma.j.issn.1003-9406.2018.03.001
发表时间：
2018-06-10
期刊：
Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics
影响因子：
--
作者：
Yang, Ke;Zeng, Sheng;Wang, Junling
通讯作者：
Wang, Junling
影响因子：
2.2
作者：
Sakai, Haruya;Yoshida, Kunihiro;Shimizu, Yusaku;Morita, Hiroshi;Ikeda, Shu-ichi;Matsumoto, Naomichi
通讯作者：
Matsumoto, Naomichi