Studies of Aminoacyl-tRNA Synthetase Mutations Causing Progressive Microcephaly

氨酰基-tRNA 合成酶突变导致进行性小头畸形的研究

• 批准号: 9751423
• 负责人: JIQIANG LING
• 金额: $ 24.76万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751423
• 关键词: Affect; Amino Acyl Transfer RNA; Amino Acyl-tRNA Synthetases; Aminoacylation; Apoptosis; Atrophic; Biochemical; CRISPR/Cas technology; Candidate Disease Gene; Cell Line; Cell Survival; Cells; Cellular Structures; Central Nervous System Diseases; Cerebrum; Collection; Complement; Cryoelectron Microscopy; Defect; Diffuse; Disease; Disease Progression; Enzymes; Eukaryotic Cell; Future; Genes; Genetic; Genetic Transcription; Growth; Head; Human; Human Genetics; Impairment; In Vitro; Lead; Length; Microcephaly; Mitochondria; Mus; Mutation; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurons; Neuropathy; Pathogenicity; Patients; Process; Protein Biosynthesis; Quality Control; Reporting; Resources; Ribosomes; Sampling; Seizures; Serine-tRNA Ligase; Severe Acute Respiratory Syndrome; Structure; Testing; Therapeutic Intervention; Toxic effect; Transfer RNA; Translations; United States; Work; Yeasts; cell growth; disease-causing mutation; experimental study; genome sequencing; human disease; induced pluripotent stem cell; insight; mutant; nervous system disorder; novel; protein misfolding; stem

PROJECT SUMMARY Microcephaly refers to a neurodevelopmental condition with smaller than expected head size and affects approximately 1 in 1,000 new born babies in the United States. Severe progressive microcephaly is also accompanied with neurodegeneration and seizures. Recent studies reveal that recessive mutations in aminoacyl-tRNA synthetases, a group of essential enzymes required for protein synthesis, cause progressive microcephaly. How such mutations lead to cellular toxicity and disorder of the central nervous system remains to be defined. Our previous work has identified disease-causing mutations in glutaminyl- (QARS) and alanyl- (AARS) tRNA synthetases in microcephaly patients, and suggests that such mutations lead to both decreased aminoacylation efficiency and protein misfolding. We have also identified a novel candidate gene causing progressive microcephaly, which tryptophanyl- (WARS) tRNA synthetases. In the proposed work, we will generate patient-derived lymphoblastoid and induced pluripotent stem cell lines, as well as yeast and neuronal cell lines carrying pathogenic mutations. The resulting cells will be used to determine: (1) the impact of QARS mutations on protein synthesis and cellular toxicity; (2) the impact of aminoacylation and editing defects in AARS; and (3) the effects of mutations in WARS and seryl-tRNA synthetase associated with microcephaly on aminoacylation and protein misfolding. This work will reveal the cellular toxicity of defective protein synthesis and provide insights into the genetic causes of microcephaly. The various cell lines developed in this study will also be valuable for future studies of protein synthesis defects and the mechanism of protein synthesis quality control.

项目摘要 小头畸形是指比预期头大小的神经发育状况，并且会影响 在美国，大约有1,000名新生婴儿。严重的进行性小头畸形也是 伴随着神经变性和癫痫发作。最近的研究表明，隐性突变 氨基酰基-TRNA合成酶是蛋白质合成所需的一组必需酶 小头畸形。这种突变如何导致中枢神经系统的细胞毒性和混乱 定义。我们以前的工作已经确定了谷氨酰胺基（QARS）和丙酰基 - 引起疾病的突变 （AARS）小头畸形患者中的tRNA合成酶，并表明这种突变导致两者都降低 氨基化效率和蛋白质错误折叠。我们还确定了一个新的候选基因，导致 渐进性的小头，色氨酸 - （战争）tRNA合成酶。在拟议的工作中，我们将 产生患者来源的淋巴母细胞和诱导多能干细胞系，以及酵母和神经元 带有致病突变的细胞系。所得细胞将用于确定：（1）QARS的影响 蛋白质合成和细胞毒性的突变； （2）氨基化和编辑缺陷的影响 Aars; （3）与小头畸形相关的战争中突变和Seryl-tRNA合成酶对 氨基酰化和蛋白质错误折叠。这项工作将揭示缺陷蛋白质合成的细胞毒性 并提供有关小头畸形遗传原因的见解。这项研究中开发的各种细胞系将 对于蛋白质合成缺陷的未来研究和蛋白质合成质量的机制也很有价值 控制。