为了深入了解这种分子机制，课题组人员比较了血液中体细胞扩增和体细胞扩增驱动的HD临床表型的全基因组关联研究。小组发现体细胞扩张是由错配修复相关的过程驱动的，该过程的遗传修饰和后果显示出意想不到的复杂性，包括细胞类型特异性。非DNA修复基因进一步改变了HD的临床轨迹，这些基因对认知和运动功能障碍的测量有不同的影响。除了共享（DNA修复基因MSH3， PMS2和FAN1）和不同的反式修饰因子外，HTT中一个同义的CAG邻近变异显著地加速运动发作而不增加躯体扩张，而顺式作用的5' -非翻译区变异促进血液重复扩增而不影响临床HD。他们的发现与DNA重复扩增的治疗性抑制直接相关，并为HD的致病机制提供了体细胞扩增之外的额外线索。
据了解，HTT中遗传的、扩增的CAG重复序列进一步进行体细胞扩增以诱导亨廷顿病（HD）。
附：英文原文
Title: Genetic modifiers of somatic expansion and clinical phenotypes in Huntington’s disease highlight shared and tissue-specific effects
Author: James F. Gusella.
Issue&Volume: 2025-06-09
Abstract: An inherited, expanded CAG repeat in HTT undergoes further somatic expansion to cause Huntington’s disease (HD). To gain insights into this molecular mechanism, we compared genome-wide association studies of somatic expansion in blood and somatic expansion-driven HD clinical phenotypes. Here, we show that somatic expansion is driven by a mismatch repair-related process whose genetic modification and consequences show unexpected complexity, including cell-type specificity. The HD clinical trajectory is further modified by non-DNA repair genes that differentially influence measures of cognitive and motor dysfunction. In addition to shared (DNA repair genes MSH3, PMS2 and FAN1) and distinct trans-modifiers, a synonymous CAG-adjacent variant in HTT dramatically hastens motor onset without increasing somatic expansion, while a cis-acting 5′-untranslated region variant promotes blood repeat expansion without influencing clinical HD. Our findings are directly relevant to the therapeutic suppression of expansion in DNA repeat disorders and provide additional clues to HD pathogenic mechanisms beyond somatic expansion.
DOI: 10.1038/s41588-025-02191-5
Source: https://www.nature.com/articles/s41588-025-02191-5
Nature Genetics：《自然—遗传学》，创刊于1992年。隶属于施普林格·自然出版集团，最新IF：41.307
官方网址：https://www.nature.com/ng/
投稿链接：https://mts-ng.nature.com/cgi-bin/main.plex
本期文章：《自然—遗传学》：Online/在线发表
