FMR1 locus isoforms: potential biomarker candidates in fragile X-associated tremor/ataxia syndrome (FXTAS)
FMR1 locus isoforms: potential biomarker candidates in fragile X-associated tremor/ataxia syndrome (FXTAS)
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DOI：
10.1038/s41598-020-67946-y
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发表时间：
2020-07-06
影响因子：
4.6
通讯作者：
Tassone, Flora
中科院分区：
文献类型：
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作者：
Zafarullah, Marwa;Tang, Hiu-Tung;Tassone, Flora
脆性X相关震颤/共济失调综合征（FXTAS）是一种迟发性成人神经退行性疾病，影响脆性X智力低下（FMR 1）基因中55-200 CGG重复的前突变等位基因的男性和女性携带者的运动和认知。目前尚不清楚前突变等位基因的个体携带者是否以及何时会发展为FXTAS，因为临床评估无法在明显的神经系统症状出现之前识别出处于风险中的携带者。本研究的主要目的是研究FMR 1基因座的选择性剪接景观，并与首次纵向研究中招募的具有前突变等位基因的男性个体的大脑测量结果相结合，与年龄匹配的健康男性对照组进行比较，目的是确定用于早期诊断，疾病预测和FXTAS进展的生物标志物。我们的研究结果表明，FMR 1 mRNA亚型，包括Iso 4/4 b，Iso 10/10 b，以及ASFMR 1 mRNA Iso 131 bp的表达增加，与非携带者健康对照相比，存在于突变前携带者中。更具体地说，我们观察到编码截短蛋白的Iso 4/4 b和Iso 10/10 b的表达更高，仅在那些随时间推移出现FXTAS症状的前突变携带者中，与非携带者健康对照相比，这表明在疾病发展中的潜在作用。此外，我们发现这些分子变化与脑形态学的各种测量结果显著相关，包括小脑中脚（MCP）、上级小脑脚（SCP）、脑桥和中脑，表明它们对FXTAS发病机制的潜在贡献。有趣的是，在访视1和访视2时观察到的Iso 4/4 b的高表达水平，发现仅在随时间发展FXTAS的那些个体中与平均MCP宽度的降低相关，这表明它们作为FXTAS早期诊断的潜在生物标志物的作用。
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.