PDF(Pubmed)
Abstract：
Expanded CAG repeats in coding regions of different genes are the most common cause of dominantly inherited spinocerebellar ataxias (SCAs). These repeats are unstable through the germline, and larger repeats lead to earlier onset. We measured somatic expansion in blood samples collected from 30 SCA1, 50 SCA2, 74 SCA3, and 30 SCA7 individuals over a mean interval of 8.5 years, along with postmortem tissues and fetal tissues from SCA1, SCA3, and SCA7 individuals to examine somatic expansion at different stages of life. We showed that somatic mosaicism in the blood increases over time. Expansion levels are significantly different among SCAs and correlate with CAG repeat lengths. The level of expansion is greater in individuals with SCA7 who manifest disease compared to that of those who do not yet display symptoms. Brain tissues from SCA individuals have larger expansions compared to the blood. The cerebellum has the lowest mosaicism among the studied brain regions, along with a high expression of ATXNs and DNA repair genes. This was the opposite in cortices, with the highest mosaicism and lower expression of ATXNs and DNA repair genes. Fetal cortices did not show repeat instability. This study shows that CAG repeats are increasingly unstable during life in the blood and the brain of SCA individuals, with gene- and tissue-specific patterns.
摘要：
在不同基因的编码区中扩增的CAG重复是显性遗传脊髓小脑共济失调（SCA）的最常见原因。这些重复序列通过种系是不稳定的，更大的重复导致更早的发作。我们测量了在平均8.5年的时间间隔内从30个SCA1，50个SCA2，74个SCA3和30个SCA7个体收集的血液样本中的体细胞扩增，以及来自SCA1，SCA3和SCA7个体的死后组织和胎儿组织，以检查生命不同阶段的体细胞扩张。我们表明，随着时间的推移，血液中的躯体镶嵌性增加。SCA之间的扩增水平显着不同，并且与CAG重复长度相关。与那些还没有表现出症状的患者相比,表现出疾病的SCA7患者的扩张水平更高。与血液相比,来自SCA个体的脑组织具有更大的扩张。小脑在所研究的大脑区域中镶嵌性最低，随着ATXNs和DNA修复基因的高表达。这在皮质上是相反的，具有最高的镶嵌性和较低的ATXNs和DNA修复基因的表达。胎儿皮质没有表现出重复的不稳定性。这项研究表明，CAG重复在SCA个体的血液和大脑中的生命过程中越来越不稳定，具有基因和组织特异性模式。
