The fragile X premutation is defined by the expansion of the CGG trinucleotide repeat at the 5′ UTR of the FMR1 gene to between 55 and 200 repeats, while repeat tracks longer than 200 are defined as full mutations. Men carrying a premutation are at increased risk for fragile X-associated tremor/ataxia syndrome (FXTAS); those with > 200 repeats have fragile X syndrome, a common genetic form of intellectual disabilities. In our study, we tested the hypothesis that men carrying a fragile X premutation or full mutation are “biologically older”, as suggested by the associated age-related disorder in the presence of the fragile X premutation or the altered cellular pathology that affects both the fragile X premutation and full mutation carriers. Thus, we predicted that both groups would have shorter telomeres than men carrying the normal size repeat allele. Using linear regression models, we found that, on average, premutation carriers had shorter telomeres compared with non-carriers (n = 69 vs n = 36; p = 0.02) and that there was no difference in telomere length between full mutation carriers and non-carriers (n = 37 vs n = 29; p > 0.10). Among premutation carriers only, we also asked whether telomere length was shorter among men with vs without symptoms of FXTAS (n = 28 vs n = 38 and n = 27 vs n = 41, depending on criteria) and found no evidence for a difference (p > 0.10). Previous studies have shown that the premutation is transcribed whereas the full mutation is not, and the expanded repeat track in FMR1 transcript is thought to lead to the risk for premutation-associated disorders. Thus, our data suggest that the observed premutation-only telomere shortening may be a consequence of the toxic effect of the premutation transcript and suggest that premutation carriers are “biologically older” than men carrying the normal size allele in the same age group.

脆弱的 X 前突变由FMR1的 5' UTR 处的 CGG 三核苷酸重复序列的扩展定义基因重复 55 到 200 次，而重复轨迹超过 200 次被定义为完全突变。携带前突变的男性患脆性 X 相关震颤/共济失调综合征 (FXTAS) 的风险增加；重复次数大于 200 的人患有脆性 X 综合征，这是一种常见的智力障碍遗传形式。在我们的研究中，我们检验了携带脆弱 X 前突变或完全突变的男性在“生物学上更老”的假设，正如在脆弱 X 前突变或细胞病理改变的情况下存在的相关年龄相关疾病所暗示的那样脆性 X 前突变和全突变携带者。因此，我们预测两组的端粒都比携带正常大小重复等位基因的男性短。使用线性回归模型，我们发现，平均而言，n  = 69 vs n  = 36；p  = 0.02）并且完全突变携带者和非携带者之间的端粒长度没有差异（n  = 37 vs n  = 29；p  > 0.10）。仅在前突变携带者中，我们还询问了有和没有 FXTAS 症状的男性的端粒长度是否更短（n  = 28 vs n  = 38 和n  = 27 vs n  = 41，取决于标准）并且没有发现差异的证据（p  > 0.10）。以前的研究表明，前突变被转录而完整突变没有，FMR1 中扩展的重复轨迹转录本被认为会导致前突变相关疾病的风险。因此，我们的数据表明，观察到的仅前突变端粒缩短可能是前突变转录本毒性作用的结果，并表明前突变携带者比携带正常大小等位基因的男性在“生物学上更老”。