Translation of GGC repeats into a toxic polyglycine protein in oculopharyngodistal myopathy type 2

作者：Kexin Jiao, Xinyu Chen, Mengye Cao, Jialong Zhang, Xingyu Xia, Xinyu Gu, Xilu Wang, Huahua Zhong, Dongyue Yue, Mingshi Gao, Nachuan Cheng, Sushan Luo, Wenbo Yu, Weijun Pan, Chongbo Zhao, Tao Wang, Wenhua Zhu, Jianying Xi · 发表于：Brain · 年份：2025 · DOI：10.1093/brain/awaf390 · 被引用次数：4 · 研究领域：Genetic Neurodegenerative Diseases、Microtubule and mitosis dynamics、Glycogen Storage Diseases and Myoclonus

GGC repeat expansions in the 5' untranslated region of the GIPC1 gene have been implicated in the pathogenesis of oculopharyngodistal myopathy type 2 (OPDM2). To investigate the underlying mechanism, we generated a series of reporter constructs to confirm the translation product of GIPC1 expanded GGC repeats. We also developed a specific antibody targeting the predicted N-terminus of the predominant translation product. Its expression and toxicity were validated in patient-derived induced pluripotent stem cell-derived myotubes and a zebrafish model. Here, we demonstrate that the expanded GGC repeats undergo repeat-associated non-AUG (RAN) translation in multiple reading frames, predominantly generating a polyglycine-containing protein (uGIPC1polyG) initiated at an upstream CTG codon. These polyG-containing proteins aggregate and form intranuclear and cytoplasmic p62/ubiquitin-positive inclusions, which are pathogenic hallmarks of OPDM2. The translation of GGC repeats into a polyG protein also causes mitochondrial dysfunction and disrupts nuclear lamina architecture, thereby inducing cytotoxicity and apoptosis in cell lines, including HEK293T cells, fibroblasts and induced pluripotent stem cell-derived myotubes from OPDM2 patients. Additionally, the zebrafish model exhibits developmental malformation and compromised locomotor function, demonstrating the in vivo toxicity of uGIPC1polyG. These findings suggest that the translation of expanded GGC repeats into a toxic polyG prote...