Trinucleotide repeats in DNA exhibit a dual nature due to their inherent instability. While their rapid expansion can diversify gene expression during evolution, exceeding a certain threshold can lead to diseases such as Huntington’s disease (HD), a neurodegenerative condition, triggered by >36 C–A–G repeats in exon 1 of the Huntingtin gene. Notably, the discovery of somatic instability (SI) of the tract allows these mutations, inherited from an affected parent, to further expand throughout the patient’s lifetime, resulting in a mosaic brain with specific neurons exhibiting variable and often extreme CAG lengths, ultimately leading to their death. Genome-wide association studies have identified genetic variants—both cis and trans, including mismatch repair modifiers—that modulate SI, as shown in blood cells, and influence HD’s age of onset. This review will explore the evidence for SI in HD and its role in disease pathogenesis, as well as the therapeutic implications of these findings. We conclude by emphasizing the urgent need for reliable methods to quantify SI for diagnostic and prognostic purposes.

中文翻译：

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当重复不再 iuvant：亨廷顿病中 CAG 三联体的体细胞不稳定


DNA 中的三核苷酸重复序列由于其固有的不稳定性而表现出双重性质。虽然它们的快速扩增可以在进化过程中使基因表达多样化，但超过一定的阈值会导致亨廷顿病 （HD） 等疾病，这是一种由亨廷顿基因外显子 1 中的 >36 C-A-G 重复触发的神经退行性疾病。值得注意的是，发现肠道体细胞不稳定性 （SI） 后，这些从受影响父母那里遗传的突变在患者的一生中进一步扩大，导致马赛克大脑具有特定神经元表现出可变且通常极端的 CAG 长度，最终导致他们死亡。全基因组关联研究已经确定了调节 SI 的遗传变异——顺式和反式，包括错配修复修饰剂——如血细胞所示，并影响 HD 的发病年龄。本综述将探讨 HD 中 SI 的证据及其在疾病发病机制中的作用，以及这些发现的治疗意义。我们最后强调迫切需要可靠的方法来量化 SI 以用于诊断和预后目的。