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...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m6(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m6(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m6(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。展开更多
Huntington's disease(HD)is caused by a CAG repeat expansion in the huntingtin(HTT)gene.Knock-in mice carrying a CAG repeat-expanded Htt will develop HD phenotypes.Previous studies suggested dysregulated molecular ...Huntington's disease(HD)is caused by a CAG repeat expansion in the huntingtin(HTT)gene.Knock-in mice carrying a CAG repeat-expanded Htt will develop HD phenotypes.Previous studies suggested dysregulated molecular networks in a CAG length genotype-and the age-dependent manner in brain tissues from knock-in mice carrying expanded Htt CAG repeats.Furthermore,a large-scale phenome analysis defined a behavioral signature for HD genotype in knock-in mice carrying expanded Htt CAG repeats.However,an integrated analysis correlating phenotype features with genotypes(CAG repeat expansions)was not conducted previously.In this study,we revealed the landscape of the behavioral features and gene expression correlations based on 445 mRNA samples and 445 microRNA samples,together with behavioral features(396 PhenoCube behaviors and 111 NeuroCube behaviors)in Htt CAG-knock-in mice.We identified 37 behavioral features that were significantly associated with CAG repeat length including the number of steps and hind limb stand duration.The behavioral features were associated with several gene coexpression groups involved in neuronal dysfunctions,which were also supported by the single-cell RNA sequencing data in the striatum and the spatial gene expression in the brain.We also identified 15 chemicals with significant responses for genes with enriched behavioral features,most of them are agonist or antagonist for dopamine receptors and serotonin receptors used for neurology/psychiatry.Our study provides further evidence that abnormal neuronal signal transduction in the striatum plays an important role in causing HD-related phenotypic behaviors and provided rich information for the further pharmacotherapeutic intervention possibility for HD.展开更多
基金supported by the National Key Research and Development Program(2018YFC1312003)the National Natural Science Foundation(81671120,81300981)+2 种基金the Natural Science Foundation for Distinguished Young Scholars of Hunan Province(2020JJ2057)the Degree&Postgraduate Education Reform Project of Central South University(2020JGB136)the Project Program of National Clinical Research Center for Geriatric Disorders(Xiangya Hospital)(2020LCJJ13),China。
文摘目的: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m6(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m6(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m6(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。
基金This research was supported by the National Natural Science Foundation of China(No.81970839 and 81670895 to L.H.)the Department of Science and Technology of Sichuan Province,China(No.2021YFS0033 to L.H).
文摘Huntington's disease(HD)is caused by a CAG repeat expansion in the huntingtin(HTT)gene.Knock-in mice carrying a CAG repeat-expanded Htt will develop HD phenotypes.Previous studies suggested dysregulated molecular networks in a CAG length genotype-and the age-dependent manner in brain tissues from knock-in mice carrying expanded Htt CAG repeats.Furthermore,a large-scale phenome analysis defined a behavioral signature for HD genotype in knock-in mice carrying expanded Htt CAG repeats.However,an integrated analysis correlating phenotype features with genotypes(CAG repeat expansions)was not conducted previously.In this study,we revealed the landscape of the behavioral features and gene expression correlations based on 445 mRNA samples and 445 microRNA samples,together with behavioral features(396 PhenoCube behaviors and 111 NeuroCube behaviors)in Htt CAG-knock-in mice.We identified 37 behavioral features that were significantly associated with CAG repeat length including the number of steps and hind limb stand duration.The behavioral features were associated with several gene coexpression groups involved in neuronal dysfunctions,which were also supported by the single-cell RNA sequencing data in the striatum and the spatial gene expression in the brain.We also identified 15 chemicals with significant responses for genes with enriched behavioral features,most of them are agonist or antagonist for dopamine receptors and serotonin receptors used for neurology/psychiatry.Our study provides further evidence that abnormal neuronal signal transduction in the striatum plays an important role in causing HD-related phenotypic behaviors and provided rich information for the further pharmacotherapeutic intervention possibility for HD.
