Mouro Pinto Ricardo, Murtha Ryan, Azevedo António, Douglas Cameron, Kovalenko Marina, Ulloa Jessica, Crescenti Steven, Burch Zoe, Oliver Esaria, Kesavan Maheswaran, Shibata Shota, Vitalo Antonia, Mota-Silva Eduarda, Riggs Marion J, Correia Kevin, Elezi Emanuela, Demelo Brigitte, Carroll Jeffrey B, Gillis Tammy, Gusella James F, MacDonald Marcy E, Wheeler Vanessa C
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Department of Neurology, Massachusetts Hospital and Harvard Medical School, Boston, MA, USA.
Nat Genet. 2025 Feb;57(2):314-322. doi: 10.1038/s41588-024-02054-5. Epub 2025 Jan 22.
Huntington's disease, one of more than 50 inherited repeat expansion disorders, is a dominantly inherited neurodegenerative disease caused by a CAG expansion in HTT. Inherited CAG repeat length is the primary determinant of age of onset, with human genetic studies underscoring that the disease is driven by the CAG length-dependent propensity of the repeat to further expand in the brain. Routes to slowing somatic CAG expansion, therefore, hold promise for disease-modifying therapies. Several DNA repair genes, notably in the mismatch repair pathway, modify somatic expansion in Huntington's disease mouse models. To identify novel modifiers of somatic expansion, we used CRISPR-Cas9 editing in Huntington's disease knock-in mice to enable in vivo screening of expansion-modifier candidates at scale. This included testing of Huntington's disease onset modifier genes emerging from human genome-wide association studies as well as interactions between modifier genes, providing insight into pathways underlying CAG expansion and potential therapeutic targets.
亨廷顿舞蹈症是50多种遗传性重复序列扩增疾病之一，是一种由HTT基因中CAG重复序列扩增导致的常染色体显性神经退行性疾病。遗传的CAG重复序列长度是发病年龄的主要决定因素，人类遗传学研究强调，该疾病是由重复序列在大脑中进一步扩增的CAG长度依赖性倾向所驱动的。因此，减缓体细胞CAG扩增的途径有望用于疾病修饰疗法。几个DNA修复基因，特别是错配修复途径中的基因，可修饰亨廷顿舞蹈症小鼠模型中的体细胞扩增。为了鉴定体细胞扩增的新型修饰因子，我们在亨廷顿舞蹈症基因敲入小鼠中使用CRISPR-Cas9编辑技术，以便大规模地在体内筛选扩增修饰因子候选基因。这包括对来自人类全基因组关联研究的亨廷顿舞蹈症发病修饰基因进行测试，以及修饰基因之间的相互作用，从而深入了解CAG扩增的潜在途径和潜在治疗靶点。
