Modulation of the age at onset in spinocerebellar ataxia by CAG tracts in various genes
Modulation of the age at onset in spinocerebellar ataxia by CAG tracts in various genes
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DOI：
10.1093/brain/awu174
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发表时间：
2014-09-01
期刊：
影响因子：
14.5
通讯作者：
Stevanin, Giovanni
中科院分区：
文献类型：
--
作者：
du Montcel, Sophie Tezenas;Durr, Alexandra;Stevanin, Giovanni
多聚谷氨酰胺编码（CAG）n重复扩增在七个不同的基因引起脊髓小脑共济失调。虽然扩张的大小与发病年龄呈负相关，但它仅占其变异性的50-70%。为了找到其他与这种变异性有关的因素，我们对1255名有明确扩张的受影响个体进行了回归分析（脊髓小脑共济失调1、2、3、6和7型），通过欧洲脊髓小脑共济失调协会招募，以确定发病年龄是否受8个含CAG n基因的正常等位基因大小的影响。（ATXN 1 -3、6-7、17、ATN 1和HTT）。我们证实了扩展等位基因的负面影响，并检测到阈值效应反映了脊髓小脑性共济失调1型，3型和6型发病年龄和CAG大小之间的二次关联。我们还证明了扩展和正常的等位基因之间的相互作用，在反式与脊髓小脑共济失调1型，6型和7型的个人。除脊髓小脑性共济失调1型患者外，发病年龄还受其他含（CAG）n基因的影响：脊髓小脑性共济失调2型中的ATXN 7;脊髓小脑性共济失调3型中的ATXN 2、ATN 1和HTT;脊髓小脑性共济失调6型中的ATXN 1和ATXN 3;以及脊髓小脑性共济失调7型中的ATXN 3和TBP。这表明这些基因之间存在生物学关系。结果在代表460名高加索人和216名亚洲人样本的四个独立人群中部分重复;差异可能由种族或地理差异解释。由于发病年龄的变化不能完全由致病和修饰的姐妹基因的影响来解释，其他遗传或环境因素也必须在这些疾病中发挥作用。
Polyglutamine-coding (CAG)n repeat expansions in seven different genes cause spinocerebellar ataxias. Although the size of the expansion is negatively correlated with age at onset, it accounts for only 50-70% of its variability. To find other factors involved in this variability, we performed a regression analysis in 1255 affected individuals with identified expansions (spinocerebellar ataxia types 1, 2, 3, 6 and 7), recruited through the European Consortium on Spinocerebellar Ataxias, to determine whether age at onset is influenced by the size of the normal allele in eight causal (CAG) n-containing genes (ATXN1-3, 6-7, 17, ATN1 and HTT). We confirmed the negative effect of the expanded allele and detected threshold effects reflected by a quadratic association between age at onset and CAG size in spinocerebellar ataxia types 1, 3 and 6. We also evidenced an interaction between the expanded and normal alleles in trans in individuals with spinocerebellar ataxia types 1, 6 and 7. Except for individuals with spinocerebellar ataxia type 1, age at onset was also influenced by other (CAG) n-containing genes: ATXN7 in spinocerebellar ataxia type 2; ATXN2, ATN1 and HTT in spinocerebellar ataxia type 3; ATXN1 and ATXN3 in spinocerebellar ataxia type 6; and ATXN3 and TBP in spinocerebellar ataxia type 7. This suggests that there are biological relationships among these genes. The results were partially replicated in four independent populations representing 460 Caucasians and 216 Asian samples; the differences are possibly explained by ethnic or geographical differences. As the variability in age at onset is not completely explained by the effects of the causative and modifier sister genes, other genetic or environmental factors must also play a role in these diseases.