Tezenas du Montcel Sophie, Durr Alexandra, Bauer Peter, Figueroa Karla P, Ichikawa Yaeko, Brussino Alessandro, Forlani Sylvie, Rakowicz Maria, Schöls Ludger, Mariotti Caterina, van de Warrenburg Bart P C, Orsi Laura, Giunti Paola, Filla Alessandro, Szymanski Sandra, Klockgether Thomas, Berciano José, Pandolfo Massimo, Boesch Sylvia, Melegh Bela, Timmann Dagmar, Mandich Paola, Camuzat Agnès, Goto Jun, Ashizawa Tetsuo, Cazeneuve Cécile, Tsuji Shoji, Pulst Stefan-M, Brusco Alfredo, Riess Olaf, Brice Alexis, Stevanin Giovanni
1 Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Univ Paris 06, UMR_S 1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, F-75013, Paris, France2 INSERM, UMR_S 1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, F-75013, Paris, France3 AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Biostatistics Unit, Paris, F-75013, France
4 AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Genetics and Cytogenetics, F-75013, Paris, France5 Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France.
Brain. 2014 Sep;137(Pt 9):2444-55. doi: 10.1093/brain/awu174. Epub 2014 Jun 26.
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.
七个不同基因中的聚谷氨酰胺编码（CAG）n重复扩增会导致脊髓小脑共济失调。尽管扩增大小与发病年龄呈负相关，但它仅占其变异性的50 - 70%。为了找到参与这种变异性的其他因素，我们对通过欧洲脊髓小脑共济失调联盟招募的1255名已确定扩增的受影响个体（脊髓小脑共济失调1、2、3、6和7型）进行了回归分析，以确定发病年龄是否受八个含因果（CAG）n基因（ATXN1 - 3、6 - 7、17、ATN1和HTT）中正常等位基因大小的影响。我们证实了扩增等位基因的负面影响，并在脊髓小脑共济失调1、3和6型中检测到发病年龄与CAG大小之间的二次关联所反映的阈值效应。我们还证明了脊髓小脑共济失调1、6和7型个体中扩增和正常等位基因之间的反式相互作用。除了脊髓小脑共济失调1型个体外，发病年龄还受其他含（CAG）n基因的影响：脊髓小脑共济失调2型中的ATXN7；脊髓小脑共济失调3型中的ATXN2、ATN1和HTT；脊髓小脑共济失调6型中的ATXN1和ATXN3；以及脊髓小脑共济失调7型中的ATXN3和TBP。这表明这些基因之间存在生物学关系。结果在代表460名白种人和216名亚洲样本的四个独立人群中部分得到重复；差异可能由种族或地理差异解释。由于发病年龄的变异性不能完全由致病和修饰姐妹基因的作用来解释，其他遗传或环境因素也必定在这些疾病中起作用。
