2. Academic Validation
  3. Understanding the role of NOTCH2 mutation in centronuclear myopathy

Understanding the role of NOTCH2 mutation in centronuclear myopathy

  • Mol Ther. 2025 Aug 6;33(8):3718-3732. doi: 10.1016/j.ymthe.2025.04.041.
Youxi Lin 1,  Hang Zhou 1,  Wenjun Hu 1,  Bo Gao 1,  Tongzhou Liang 2,  Jincheng Qiu 3,  Pengfei Li 4,  Yichen Que 1,  Chipiu Wong 1,  Xianjian Qiu 1,  Zhihuai Deng 1,  Huihong Shi 1,  Song Liu 1,  Jianan Chen 1,  Nianchun Liao 1,  Qihui Chen 5,  Xiaojuan Li 6,  Anjing Liang 7,  Wenjie Gao 8,  Dongsheng Huang 9
Affiliations

Affiliations

  • 1 Department of Orthopedic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510300, Guangdong, China.
  • 2 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.
  • 3 Panyu Hospital of Chinese Medicine, Department of Minimally Invasive Spine Surgery, Guangzhou 511400, Guangdong, China.
  • 4 Department of Orthopedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.
  • 5 Department of Pediatrics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510300, Guangdong, China.
  • 6 Center for Cellular and Molecular Diagnostics, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510300, Guangdong, China.
  • 7 Department of Orthopedic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510300, Guangdong, China. Electronic address: lianganj@mail.sysu.edu.cn.
  • 8 Department of Orthopedic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510300, Guangdong, China. Electronic address: gaowj7@mail.sysu.edu.cn.
  • 9 Department of Orthopedic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510300, Guangdong, China. Electronic address: hdongsh@mail.sysu.edu.cn.
PMID: 40336196 DOI: 10.1016/j.ymthe.2025.04.041
Abstract

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.

Keywords

Notch pathway; centronuclear myopathy; muscle satellite cells; rare disease.

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