Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, 95817 CA, USA.
Division of Biostatistics, School of Medicine, University of California Davis, Davis, CA, USA.
Sci Rep. 2020 Jul 6;10(1):11099. doi: 10.1038/s41598-020-67946-y.
Fragile X associated tremor/ataxia syndrome (FXTAS) is a late adult-onset neurodegenerative disorder that affects movement and cognition in male and female carriers of a premutation allele of 55-200 CGG repeats in the Fragile X mental retardation (FMR1) gene. It is currently unknown if and when an individual carrier of a premutation allele will develop FXTAS, as clinical assessment fails to identify carriers at risk before significant neurological symptoms are evident. The primary objective of this study was to investigate the alternative splicing landscape at the FMR1 locus in conjunction with brain measures in male individuals with a premutation allele enrolled in a very first longitudinal study, compared to age-matched healthy male controls, with the purpose of identifying biomarkers for early diagnosis, disease prediction and, a progression of FXTAS. Our findings indicate that increased expression of FMR1 mRNA isoforms, including Iso4/4b, Iso10/10b, as well as of the ASFMR1 mRNAs Iso131bp, are present in premutation carriers as compared to non-carrier healthy controls. More specifically, we observed a higher expression of Iso4/4b and Iso10/10b, which encode for truncated proteins, only in those premutation carriers who developed symptoms of FXTAS over time as compared to non-carrier healthy controls, suggesting a potential role in the development of the disorder. In addition, we found a significant association of these molecular changes with various measurements of brain morphology, including the middle cerebellar peduncle (MCP), superior cerebellar peduncle (SCP), pons, and midbrain, indicating their potential contribution to the pathogenesis of FXTAS. Interestingly, the high expression levels of Iso4/4b observed both at visit 1 and visit 2 and found to be associated with a decrease in mean MCP width only in those individuals who developed FXTAS over time, suggests their role as potential biomarkers for early diagnosis of FXTAS.
脆性 X 相关震颤共济失调综合征（FXTAS）是一种迟发性成年发病的神经退行性疾病，影响男性和女性脆性 X 智力低下 1 号基因（FMR1）前突变等位基因 55-200CGG 重复的携带者的运动和认知能力。目前尚不清楚个体前突变等位基因携带者何时会发展为 FXTAS，因为临床评估无法在明显的神经症状出现之前识别出有风险的携带者。本研究的主要目的是调查与大脑测量相结合的 FMR1 基因座的选择性剪接图谱，与参加首次纵向研究的前突变等位基因男性个体相比，与年龄匹配的健康男性对照相比，目的是确定早期诊断、疾病预测和 FXTAS 进展的生物标志物。我们的研究结果表明，与非携带者健康对照相比，前突变携带者的 FMR1mRNA 异构体，包括 Iso4/4b、Iso10/10b 以及 ASFMR1mRNA Iso131bp 的表达增加。更具体地说，我们观察到 Iso4/4b 和 Iso10/10b 的表达更高，这些异构体编码截短的蛋白质，仅在前突变携带者随着时间的推移出现 FXTAS 症状时，与非携带者健康对照相比，这表明它们在疾病的发展中可能起作用。此外，我们发现这些分子变化与大脑形态的各种测量值之间存在显著关联，包括小脑中脚（MCP）、小脑上脚（SCP）、脑桥和中脑，表明它们可能有助于 FXTAS 的发病机制。有趣的是，在随访 1 和随访 2 中观察到 Iso4/4b 的高表达水平，并且发现与随着时间的推移发展为 FXTAS 的个体的 MCP 宽度平均值降低相关，这表明它们作为 FXTAS 早期诊断的潜在生物标志物的作用。
