The role of ataxin 10 in the pathogenesis of spinocerebellar ataxia type 10
The role of ataxin 10 in the pathogenesis of spinocerebellar ataxia type 10
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DOI：
10.1212/01.wnl.0000231140.26253.eb
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发表时间：
2006-08-22
期刊：
影响因子：
9.9
通讯作者：
Ashizawa, T.
中科院分区：
文献类型：
--
作者：
Wakamiya, M.;Matsuura, T.;Ashizawa, T.
背景：脊髓小脑性共济失调10型(SCA10)是一种常染色体显性遗传性疾病，以小脑性共济失调和癫痫发作为特征。SCA10是由ataxin 10(ATXN10)基因内含子9的ATTCT五核苷酸重复序列扩大引起的，编码一个约55kd的未知功能蛋白质。然而，这种突变是如何导致SCA10的还不清楚。方法：为了了解SCA10的致病机制，作者进行了一系列实验，以研究重复序列扩张对ATXN10基因转录和RNA加工的影响。此外，我们还建立了Sca10(小鼠ataxin 10同源基因)缺失的小鼠，并研究了Sca10基因剂量对小脑的作用。结果：突变的ATXN10等位基因在正常水平转录，含有扩展重复序列的Pre-mRNA在患者来源的细胞中正常处理。Sca10基因缺失的小鼠表现出胚胎致死性。结论：ATXN10功能的简单获得或功能丧失不是脊髓小脑型共济失调10型的主要致病机制。
Background: Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant disorder characterized by cerebellar ataxia and seizures. SCA10 is caused by an expansion of an ATTCT pentanucleotide repeat in intron 9 of the ataxin 10 (ATXN10) gene encoding an approximately 55-kd protein of unknown function. However, how this mutation leads to SCA10 is unknown. Methods: In an effort to understand the pathogenic mechanism of SCA10, the authors conducted a series of experiments to address the effect of repeat expansion on the transcription and RNA processing of the ATXN10 gene. In addition, we generated Sca10 (mouse ataxin 10 homolog)-null mice and addressed the role of Sca10 gene dosage on the cerebellum. Results: Mutant ATXN10 allele is transcribed at the normal level, and the pre-mRNA containing an expanded repeat is processed normally in patient-derived cells. Sca10-null mice exhibited embryonic lethality. Heterozygous mutants were overtly normal and did not develop SCA10 phenotype Conclusion: A simple gain of function or loss of function of ATXN10 is unlikely to be the major pathogenic mechanism contributing to the spinocerebellar ataxia type 10 phenotype.