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ATXN1：扩大ALS中多聚谷氨酰胺重复序列的范围ATXN1: expanding the spectrum of polyglutamine repeats in ALS |
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| 课程网址: | http://videolectures.net/encals2017_tazelaar_polyglutamine_repeat... |
| 主讲教师: | Gijs Tazelaar |
| 开课单位: | 荷兰乌得勒支大学 |
| 开课时间: | 2017-07-21 |
| 课程语种: | 英语 |
| 中文简介: |  |
| 课程简介: | Objective: Polyglutamine proteins can cause a wide range of neurodegenerative disorders upon long-range expansions such as Huntington’s disease and spinocerebellar ataxia (SCA). Intermediate length of the polyglutamine coding CAG/CAA trinucleotide repeat in the ATXN2 gene was shown to be a risk factor for amyotrophic lateral sclerosis (ALS). Involvement of other CAG-repeat genes has only been moderately investigated or reported, although an association was found with intermediate length in the ATXN1 in a small Italian cohort after discovery of a pedigree with co-occurrence of ALS and SCA1 disease. After identification of a similar pedigree, we set out to investigate the frequency of ATXN1 intermediate expansions in a large international cohort of ALS patients and controls. Methods: We screened the ATXN1 CAG/CAT trinucleotide repeat length via PCR in DNA of 2,742 ALS patients and 2,374 controls from 4 different countries (Belgium, France, Ireland and The Netherlands). PCR-fragment repeat size was additionally validated using Sanger sequencing in a subset (N=850) of the data. An intermediate cut-off was determined via control distribution and was found to be at 33 CAG/CAT repeats and higher. Results: We found 242 (11.4%) intermediate expansion carriers in control individuals and 333 (13.8%) in ALS patients. Meta-analysis of the frequencies in the 4 different cohorts showed significantly more expanded repeats in ATXN1 in ALS patients compared to controls (p = 0.006, one sided) with an odds ratio of 1.25 (95% CI: 1.05- 1.50). Interpretation: Similar to ATXN2, there is an association with an increased length of CAG(/CAT) trinucleotide repeats in ATXN1 and ALS. Interestingly, in contrast to ATXN2, we found a relative high frequency of intermediate expansions in ATXN1 in both ALS (1-2% in ATXN2 vs 6-7% in ATXN1) and control individuals (0.3-0.4% in ATXN2 vs 5-6% in ATXN1). This fits with the hypothesis that intermediate polyglutamine expansions might not be causative but pose an increased risk for developing ALS. However, this overall risk in ATXN1 seems to be smaller compared to intermediate carriers in ATXN2 (OR 3.06 in ATXN2 vs OR 1.25 in ATXN1). Future experiments will focus on both the similarities between ATXN1 and ATXN2, such as TDP-43 binding capacity, as well as the differences, such as the CAT-interruptions in ATXN1, to further elucidate the role of polyglutamine expansions in ALS. |
| 关 键 词: | 多聚谷氨酰胺蛋白; 神经退行性疾病; ALS |
| 课程来源: | 视频讲座网 |
| 数据采集: | 2021-12-10：zkj |
| 最后编审: | 2021-12-10：zkj |
| 阅读次数: | 91 |