Cattaneo Elena, Scalzo Davide, Zobel Martina, Iennaco Raffaele, Maffezzini Camilla, Besusso Dario, Maestri Simone
Department of Biosciences, University of Milan, street Giovanni Celoria, 26, 20133, Milan, Italy.
INGM, Fondazione Istituto Nazionale Genetica Molecolare 'Romeo ed Enrica Invernizzi', street Francesco Sforza, 35, 20122, Milan, Italy.
Nucleic Acids Res. 2025 Jan 7;53(1). doi: 10.1093/nar/gkae1204.
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.
由于其固有的不稳定性，DNA中的三核苷酸重复序列具有双重性质。虽然它们在进化过程中的快速扩增可以使基因表达多样化，但超过一定阈值会导致疾病，如亨廷顿舞蹈病（HD），这是一种神经退行性疾病，由亨廷顿基因第1外显子中超过36个CAG重复序列引发。值得注意的是，该区域体细胞不稳定性（SI）的发现使得这些从患病亲本遗传的突变在患者的一生中进一步扩增，导致大脑呈现镶嵌式，特定神经元表现出可变且往往极长的CAG长度，最终导致它们死亡。全基因组关联研究已经确定了顺式和反式的遗传变异，包括错配修复修饰因子，这些因子在血细胞中可调节SI，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。我们强调迫切需要可靠的方法来定量SI以用于诊断和预后目的，以此作为结论。
