Lin Youxi, Zhou Hang, Hu Wenjun, Gao Bo, Liang Tongzhou, Qiu Jincheng, Li Pengfei, Que Yichen, Wong Chipiu, Qiu Xianjian, Deng Zhihuai, Shi Huihong, Liu Song, Chen Jianan, Liao Nianchun, Chen Qihui, Li Xiaojuan, Liang Anjing, Gao Wenjie, Huang Dongsheng
Department of Orthopedic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510300, Guangdong, China.
Musculoskeletal Research Laboratory, Department of Orthopedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR 999077, China.
Mol Ther. 2025 Aug 6;33(8):3718-3732. doi: 10.1016/j.ymthe.2025.04.041. Epub 2025 May 6.
NOTCH2 is a widely expressed protein that plays a crucial role in the normal development and function of various tissues, including skeletal muscle. This study focused on a pedigree with centronuclear myopathy, primarily characterized by muscle weakness and centralized nuclei, and identified the autosomal recessive NOTCH2 p.I1689F mutation through whole-exome sequencing. Using a homologous mutant mouse model, several defects were identified that elucidate the muscle phenotype. These defects include a reduction in Pax7-expressing, proliferating myoblasts and the functional consequences of this reduction. In vitro studies demonstrated that the Notch2 mutation impaired proliferation and causing premature differentiation of myogenic progenitor cells. Mechanistically, the Notch2 mutation resulted in decreased production of the Notch2 intracellular domain from γ-secretase S3 cleavage, which affected the function of Pax7 cells through the Notch2-Hey1-MyoD axis. Overall, our findings reveal impaired muscle regeneration in mice with the Notch2 mutation, contributing to the understanding of centronuclear myopathy by identifying a previously unreported gene and mutation site of NOTCH2.
NOTCH2是一种广泛表达的蛋白质，在包括骨骼肌在内的各种组织的正常发育和功能中起着关键作用。本研究聚焦于一个以中央核性肌病为主的家系，其主要特征为肌肉无力和细胞核集中，并通过全外显子组测序鉴定出常染色体隐性NOTCH2 p.I1689F突变。使用同源突变小鼠模型，发现了几个可解释肌肉表型的缺陷。这些缺陷包括表达Pax7的增殖成肌细胞减少以及这种减少的功能后果。体外研究表明，Notch2突变损害了增殖并导致成肌祖细胞过早分化。从机制上讲，Notch2突变导致γ-分泌酶S3切割产生的Notch2细胞内结构域减少，这通过Notch2-Hey1-MyoD轴影响了Pax7细胞的功能。总体而言，我们的研究结果揭示了Notch2突变小鼠的肌肉再生受损，通过鉴定一个先前未报道的NOTCH2基因和突变位点，有助于对中央核性肌病的理解。
