Objectives: Spinocerebellar ataxia type 2 (SCA2) is one of the most common autosomal dominant ataxias in the world. Several reports revealed that CAG repeats in some polyQ-containing genes may affect the age at onset (AAO) of patients with SCA2, however, little studies were conducted among Chinese patients with SCA2. Thus, the aim of this study is to evaluate the effect of CAG repeats on the AAO of patients with SCA2 in China.
Methods: A total of 119 patients with SCA2 were enrolled and were divided into 2 groups according to their major phenotype: 17 patients from 9 families with Parkinson's syndrome were grouped as the Parkinson's disease-SCA2 (PD-SAC2); 91 patients from 66 SCA2 families and 11 sporadic SCA2 patients were grouped as the ataxia-SCA2 (A-SCA2). Blood samples were obtained from the subjects, and the CAG repeat length in ATXN2 and other (CAG)n-containing genes was screened using fluorescent PCR. The Spearman's rank correlation between the CAG repeat length in (CAG)n-containing genes and AAO was analyzed. Regression analysis was performed to investigate whether the CAG repeat length could explain the variant of AAO. A t-test was used to compare the difference of CAG repeat length in (CAG)n-containing genes between the PD-SAC2 and A-SCA2 groups.
Results: The CAG repeat length in the longer allele of ATXN2 was negatively correlated with AAO of SCA2 (R=-0.251, P<0.05), and the CAG repeat length could explain 41.7% of the variation of AAO. AAO negatively correlated with the CAG repeat length in the shorter allele of ATXN7 (R=-0.251, P=0.006) or in the longer allele of TBP gene (R=-0.197, P=0.034). A tendency of delay in the AAO was also observed in patients with SCA2 carrying the CAG repeat within the ATXN3, CACNA1A, ATXN7, TBP, and RAI1. In addition, we found that the CAG repeat length in ATXN7 and ATXN2 between the A-SCA2 and the PD-SCA2 groups was significantly different (both P<0.05).
Conclusions: The CAG repeat in ATXN2 is a major genetic factor for the AAO of patients with SCA2 in China. The CAG repeat length in ATXN3, CACNA1A, ATXN7, TBP, and RAI1 genes might be a potential factor associated with the AAO of SCA2. The CAG repeat in ATXN7 might be a potential factor affecting the Parkinson's syndrome in SCA2.
目的: 脊髓小脑共济失调2型(spinocerebellar ataxia type 2，SCA2)是世界上最常见的常染色体显性遗传的共济失调之一。多篇报道显示某些含polyQ基因的CAG重复序列可能影响SCA2患者的发病年龄(age at onset，AAO)，但在中国SCA2患者中进行研究的较少。因此，本研究旨在探讨CAG重复序列的长度对中国SCA2患者AAO的影响。方法: 纳入119例SCA2患者，根据其主要表型分为2组：17例来自9个帕金森综合征家庭的SCA2患者作为帕金森病-SCA2(Parkinson's disease-SCA2，PD-SAC2)组，91例来自66个SCA2家庭和11例散发的SCA2患者作为共济失调-SAC2(ataxia-SCA2，A-SCA2)组。使用荧光PCR筛查ATXN2和其他含(CAG)n基因中CAG重复序列的长度。采用Spearman's等级相关的方法分析含(CAG)n基因中CAG重复序列的长度与AAO的相关性，采用回归分析评估CAG重复序列的长度对AAO变异的贡献，采用t检验比较PD-SAC2组与A-SCA2组间含(CAG)n基因中CAG重复序列的长度。结果: ATXN2基因中含较长CAG重复序列的等位基因的CAG重复序列的长度与SCA2的AAO呈负相关 (R=-0.251，P<0.05)，可解释41.7%的AAO变异。AAO与ATXN7基因中含较短CAG重复序列的等位基因(R=-0.251，P=0.006)及TBP基因中含较长CAG重复序列的等位基因(R=-0.197，P=0.034)的CAG重复序列的长度均呈负相关。在携带含CAG重复序列的ATXN3、CACNA1A、ATXN7、TBP和RAI1基因的SCA2患者中也检测到AAO延迟的趋势。此外，ATXN7基因和ATXN2基因的CAG重复序列的长度在A-SCA2组和PD-SCA2组之间的差异有统计学意义(均P<0.05)。结论: ATXN2中的CAG重复序列是影响中国SCA2患者AAO的主要遗传因素。ATXN3、CACNA1A、ATXN7、TBP和RAI1基因的CAG重复序列的长度可能是与SCA2的AAO相关的因素。ATXN7基因中的CAG重复序列的长度可能是SCA2患者表现为帕金森综合征的影响因素之一。.
目的: 脊髓小脑共济失调2型(spinocerebellar ataxia type 2，SCA2)是世界上最常见的常染色体显性遗传的共济失调之一。多篇报道显示某些含polyQ基因的CAG重复序列可能影响SCA2患者的发病年龄(age at onset，AAO)，但在中国SCA2患者中进行研究的较少。因此，本研究旨在探讨CAG重复序列的长度对中国SCA2患者AAO的影响。
方法: 纳入119例SCA2患者，根据其主要表型分为2组：17例来自9个帕金森综合征家庭的SCA2患者作为帕金森病-SCA2(Parkinson's disease-SCA2，PD-SAC2)组，91例来自66个SCA2家庭和11例散发的SCA2患者作为共济失调-SAC2(ataxia-SCA2，A-SCA2)组。使用荧光PCR筛查ATXN2和其他含(CAG)n基因中CAG重复序列的长度。采用Spearman's等级相关的方法分析含(CAG)n基因中CAG重复序列的长度与AAO的相关性，采用回归分析评估CAG重复序列的长度对AAO变异的贡献，采用t检验比较PD-SAC2组与A-SCA2组间含(CAG)n基因中CAG重复序列的长度。
结果: ATXN2基因中含较长CAG重复序列的等位基因的CAG重复序列的长度与SCA2的AAO呈负相关 (R=-0.251，P<0.05)，可解释41.7%的AAO变异。AAO与ATXN7基因中含较短CAG重复序列的等位基因(R=-0.251，P=0.006)及TBP基因中含较长CAG重复序列的等位基因(R=-0.197，P=0.034)的CAG重复序列的长度均呈负相关。在携带含CAG重复序列的ATXN3、CACNA1A、ATXN7、TBP和RAI1基因的SCA2患者中也检测到AAO延迟的趋势。此外，ATXN7基因和ATXN2基因的CAG重复序列的长度在A-SCA2组和PD-SCA2组之间的差异有统计学意义(均P<0.05)。
结论: ATXN2中的CAG重复序列是影响中国SCA2患者AAO的主要遗传因素。ATXN3、CACNA1A、ATXN7、TBP和RAI1基因的CAG重复序列的长度可能是与SCA2的AAO相关的因素。ATXN7基因中的CAG重复序列的长度可能是SCA2患者表现为帕金森综合征的影响因素之一。
Keywords: (CAG) n-containing genes; CAG repeat length; Parkinson’s syndrome; spinocerebellar ataxia type 2.