Department of Radiophysics and Nanothechnology, Kuban State University, 350040 Krasnodar, Russian Federation.
Laboratory of Problems of Stable Isotope Spreading in Living Systems, Southern Scientific Center of the Russian Academy of Sciences, 344006 Rostov-on-Don, Russian Federation.
Int J Biol Macromol. 2024 Sep;276(Pt 1):133849. doi: 10.1016/j.ijbiomac.2024.133849. Epub 2024 Jul 14.
Hereditary ataxias are one of the «anticipation diseases» types. Spinocerebral ataxia type 2 occurs when the number of CAG repeats in the coding region of the ATXN2 gene exceeds 34 or more. In healthy people, the CAG repeat region in the ATXN2 gene usually consists of 22-23 CAG trinucleotides. Mutations that increase the length of CAG repeats can cause severe neurodegenerative and neuromuscular disorders known as trinucleotide repeat expansion diseases. The mechanisms causing such diseases are associated with non-canonical configurations that can be formed in the CAG repeat region during replication, transcription or repair. This makes it relevant to study the zones of open states that arise in the region of CAG repeats under torque. The purpose of this work is to study, using mathematical modeling, zones of open states in the region of CAG repeats of the ATXN2 gene, caused by torque. It has been established that the torque effect on the 1st exon of the ATXN2 gene, in addition to the formation of open states in the promoter region, can lead to the formation of additional various sizes open states zones in the CAG repeats region. Moreover, the frequency of additional large zones genesis increases with increasing number of CAG repeats. The inverse of this frequency correlates with the dependence of the disease onset average age on the CAG repeats length. The obtained results will allow us to get closer to understanding the genetic mechanisms that cause trinucleotide repeat diseases.
遗传性共济失调是“ anticipation diseases”（ anticipation disease 是指在特定基因中的重复序列随着世代传递而逐渐延长，从而导致疾病症状的出现时间提前的疾病类型）的一种。当 ATXN2 基因编码区中的 CAG 重复次数超过 34 次或更多时，就会发生脊髓小脑性共济失调 2 型。在健康人中，ATXN2 基因的 CAG 重复区通常由 22-23 个 CAG 三核苷酸组成。增加 CAG 重复长度的突变会导致严重的神经退行性和神经肌肉疾病，称为三核苷酸重复扩展疾病。导致此类疾病的机制与非经典构象有关，这些构象在复制、转录或修复过程中可能在 CAG 重复区形成。因此，研究 CAG 重复区在扭矩作用下产生的开放状态区具有重要意义。本工作的目的是使用数学建模研究 ATXN2 基因的 CAG 重复区在扭矩作用下产生的开放状态区。研究结果表明，扭矩对 ATXN2 基因第一外显子的作用，除了在启动子区域形成开放状态外，还可以导致 CAG 重复区中形成额外的各种大小的开放状态区。此外，额外的大区域形成的频率随着 CAG 重复次数的增加而增加。这个频率的倒数与疾病平均发病年龄与 CAG 重复长度的依赖关系相关。所得结果将使我们更接近于理解导致三核苷酸重复疾病的遗传机制。
