Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Davis, California, United States of America.
PLoS One. 2011;6(7):e21728. doi: 10.1371/journal.pone.0021728. Epub 2011 Jul 19.
Fragile X associated disorders are caused by a premutation allele in the fragile X mental retardation 1 gene (FMR1) and are hypothesized to result from the toxic effect of elevated levels of expanded FMR1 transcripts. Increased levels of FMR1 mRNA have indeed been reported in premutation carriers; however the mechanism by which expanded alleles lead to elevated levels of FMR1 mRNA in premutation carriers is unknown. Within the CGG repeat tract AGG interruptions are found, generally 1-3 present in normal/intermediate alleles (6-54 CGG repeats) and usually 0-1 in premutation alleles (55-200 CGG repeats). They are present at specific locations, generally occurring after 9 or 10 uninterrupted CGG repeats [(CGG)(9)AGG(CGG)(9)AGG(CGG)(n)]. We evaluated both the number of AGG interruptions and the resulting length of the uninterrupted 3' CGG repeat pure tract in premutation alleles derived from two large cohorts of male and female carriers to determine whether the presence of AGG interruptions or the length of a pure stretch of CGG repeats influence the levels of FMR1 mRNA in blood. Our findings indicate that neither the number of AGG interruptions, nor their position along the CGG tract have a significant affect on mRNA levels in premutation carriers. We also, as expected based on previous findings, observed a highly significant correlation between CGG repeat number (as both total length and length of pure CGG stretch) and FMR1 mRNA expression levels, in both males and females. Importantly, we did not observe any significant difference in FMR1 mRNA levels in premutation carriers based on age.
脆性 X 相关障碍是由脆性 X 智力低下 1 基因 (FMR1) 的前突变等位基因引起的，据推测是由于扩增的 FMR1 转录本的毒性作用所致。在前突变携带者中确实报道了 FMR1 mRNA 水平升高；然而，扩增等位基因如何导致前突变携带者中 FMR1 mRNA 水平升高的机制尚不清楚。在 CGG 重复序列中发现了 AGG 中断，通常在正常/中间等位基因中存在 1-3 个（6-54 CGG 重复），而在前突变等位基因中通常存在 0-1 个（55-200 CGG 重复）。它们位于特定位置，通常发生在 9 个或 10 个未中断的 CGG 重复之后 [(CGG)(9)AGG(CGG)(9)AGG(CGG)(n)]。我们评估了来自两个大型男性和女性携带者队列的前突变等位基因中 AGG 中断的数量及其未中断的 3'CGG 重复纯区的长度，以确定 AGG 中断的存在或 CGG 重复纯区的长度是否影响血液中的 FMR1 mRNA 水平。我们的发现表明，AGG 中断的数量及其在 CGG 序列中的位置都不会对前突变携带者中的 mRNA 水平产生显著影响。我们还观察到，正如之前的发现所预期的那样，在男性和女性中，CGG 重复数（无论是总长度还是纯 CGG 延伸长度）与 FMR1 mRNA 表达水平之间存在高度显著的相关性。重要的是，我们没有观察到前突变携带者中 FMR1 mRNA 水平因年龄而异的任何显著差异。
