核苷酸短串联重复异常相关神经系统遗传病的新致病基因鉴定及发病机制研究

神经系统遗传病是一类主要累及神经系统的疾病，随着二代测序（NGS）技术在基因诊断方面的应用，多种致病基因得以明确，然而仍然有超过30%的遗传病患者病因未明。近年来长读长高通量测序（LRS）技术的发展，多个核苷酸短串联重复（STR）突变的基因被发现。前期，课题组利用多年积累的临床病理标本库丰富的家系资源，与北京希望组合作，通过最新LRS技术，相继发现神经元核内包涵体病和眼咽远端型肌病的STR突变新基因，并解析其致病机制。本项目将在前期基础上，综合运用LRS技术和家系连锁分析，克隆遗传性脑白质病、运动神经元病、神经肌肉病这三类遗传性神经系统疾病的STR突变新基因。从分子、细胞、果蝇模型、小鼠模型、临床标本等多个层面，综合利用分子生物学、转录组学、蛋白质组学、果蝇遗传学、高通量药物筛选等研究手段，探究STR扩增异常基因引起神经系统遗传病发生、发展的作用机理，有望为该类疾病的诊治提供理论依据。

Neurogenetic diseases are a type of diseases that mainly affect the nervous system. With the application of next-generation sequencing (NGS) technology in genetic diagnosis, a variety of disease-causing genes have been clarified. However, more than 30% of genetic disease patients have unknown causes. In recent years, with the development of long-read high-throughput sequencing (LRS) technology, genes with short tandem repeat (STR) mutations have been discovered. In the previous work, our research team used the family resources of the clinical pathological specimen library accumulated over the years, and cooperated with the Beijing Grandomics Biosciences to discover the STR mutant genes of neuronal intranuclear inclusion disease and Oculopharyngodistal myopathy through the latest LRS technology. This project will further cooperate with the Beijing Grandomics Biosciences on the basis of the previous work, and will use the LRS technology and family linkage analysis to identify the STR mutations of the three types of hereditary neurological diseases, including hereditary leukoencephalopathy, motor neuron diseases and neuromuscular diseases. From the molecular, cellular, drosophila model, transgenic mouse model, clinical specimens, comprehensively use molecular biology, transcriptomics, proteomics, fly genetic screening, high-throughput drug screening and other research methods to explore the pathogenic mechanisms underlying STR mutations in neurogenetic diseases. This work is expected to provide a theoretical basis for the diagnosis and treatment of hereditary neurological diseases.