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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要小头畸形是指头部尺寸小于预期并影响神经发育的疾病在美国，大约每 1,000 个新生儿中就有 1 个。严重的进行性小头畸形也伴有神经退行性变和癫痫发作。最近的研究表明，隐性突变氨酰-tRNA 合成酶是蛋白质合成所需的一组必需酶，可引起进行性小头畸形。这些突变如何导致细胞毒性和中枢神经系统紊乱仍然存在待定义。我们之前的工作已经确定了谷氨酰胺酰- (QARS) 和丙氨酰- 中的致病突变。 (AARS) 小头畸形患者的 tRNA 合成酶，并表明此类突变导致氨酰化效率和蛋白质错误折叠。我们还发现了一个新的候选基因进行性小头畸形，由色氨酸 (WARS) tRNA 合成酶引起。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，以及酵母和神经元携带致病突变的细胞系。生成的单元格将用于确定：(1) QARS 的影响蛋白质合成和细胞毒性的突变； (2)氨酰化和编辑缺陷的影响 AARS； (3) 与小头畸形相关的 WARS 和丝氨酰-tRNA 合成酶突变的影响氨酰化和蛋白质错误折叠。这项工作将揭示蛋白质合成缺陷的细胞毒性并提供对小头畸形遗传原因的见解。本研究中开发的各种细胞系将对于未来蛋白质合成缺陷和蛋白质合成质量机制的研究也具有重要价值控制。