Huang Xiu-Rong, Tang Bei-Sha, Jin Peng, Guo Ji-Feng
Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Mol Neurobiol. 2022 Jan;59(1):523-534. doi: 10.1007/s12035-021-02616-2. Epub 2021 Oct 31.
The human-specific gene NOTCH2NLC is primarily expressed in radial glial cells and plays an important role in neuronal differentiation and cortical neurogenesis. Increasing studies were conducted to verify the relationship between NOTCH2NLC gene and many neurological diseases, such as neuronal intranuclear inclusion disease, essential tremor, multiple system atrophy, Parkinson's disease, Alzheimer's disease, and even oculopharyngodistal myopathy. Thus, we support the concept, NOTCH2NLC-related GGC repeat expansion disorders (NRED), to summarize all diseases with the GGC repeat expansion in the 5'UTR of NOTCH2NLC gene, regardless of their various clinical phenotypes. Here, we discuss the reported cases to analyze the clinical features of NOTCH2NLC-related GGC repeat expansion disorders, including dementia, parkinsonism, peripheral neuropathy and myopathy, leukoencephalopathy, and essential tremor. In addition, we outline radiological and pathological manifestations of NOTCH2NLC-related GGC repeat expansion disorders, and then present possible mechanisms, such as toxic polyG protein, toxic repeat RNA, the GGC repeat size, and the size and types of trinucleotide interruption. Therefore, this review provides a systematic description of NOTCH2NLC-related GGC repeat expansion disorders and emphasizes the significance for understanding this type of repeat expansion disease.
人类特有的基因NOTCH2NLC主要在放射状胶质细胞中表达，在神经元分化和皮质神经发生中起重要作用。越来越多的研究致力于验证NOTCH2NLC基因与许多神经系统疾病之间的关系，如神经元核内包涵体病、特发性震颤、多系统萎缩、帕金森病、阿尔茨海默病，甚至眼咽远端肌病。因此，我们支持“NOTCH2NLC相关GGC重复扩增疾病（NRED）”这一概念，以概括所有NOTCH2NLC基因5'UTR区域存在GGC重复扩增的疾病，无论其临床表型如何。在此，我们讨论已报道的病例，以分析NOTCH2NLC相关GGC重复扩增疾病的临床特征，包括痴呆、帕金森综合征、周围神经病和肌病、白质脑病以及特发性震颤。此外，我们概述了NOTCH2NLC相关GGC重复扩增疾病的影像学和病理学表现，然后介绍了可能的机制，如毒性多聚G蛋白、毒性重复RNA、GGC重复序列长度以及三核苷酸中断的长度和类型。因此，本综述对NOTCH2NLC相关GGC重复扩增疾病进行了系统描述，并强调了理解此类重复扩增疾病的重要性。
