Genetics and Functional Studies of Autosomal Recessive Neurological Disorders

项目摘要 据世卫组织估计，神经系统疾病占全球疾病负担的6%以上。那里 有600多种神经系统疾病和认知功能障碍，也被称为智力残疾（ID）， 在这份名单中占据了突出的位置。它表现为日常社会和生活中的适应行为缺陷， 实用技能，这可能对受影响的个人及其家庭的生活产生破坏性影响。由于 其高患病率为2 - 3%，2; 3，在美国，每个人的终身护理费用在100 - 200万美元之间， 目前，4ID呈现出显著的健康负担，并且是临床水平的主要挑战。遗传因素是 涉及25 - 50% ID病例的病因。2基因和蛋白质的遗传和功能研究 ID的决定因素有助于阐明人类大脑健康发育的分子途径， 疾病然而，大量必需的分子和细胞成分的身份仍然存在 未知拟议研究的目的是确定和表征基因/蛋白质的必要性， 常染色体隐性遗传ID（ARID）。其基本原理是，识别导致ARID的致病基因变异， 阐明正常基因的功能对于理解大脑功能和发育至关重要。 用于一般神经障碍的改进的诊断工具和有效的预防和治疗剂 尤其是ID。该项目致力于NIH的使命，即产生可翻译的基础知识 减轻人类疾病的负担。本研究的目的有三：1）确定和临床表型的成员， 分离ARID的大家族; 2）鉴定新的ARID基因和基因产物; 3）确定突触的表达; 通过分析小鼠大脑中的时空表达模式， 培养的大鼠海马神经元中的突触靶向，对细胞形态和突触丰度的影响， 通过电生理学、活细胞成像和子宫内神经元细胞的突触传递和可塑性 电穿孔测定。该项目将有利地结合联合收割机人类临床评估，遗传和 与大脑发育和功能相关的功能分析。影响：拟议研究的执行将 产生临床相关的新知识，具有影响ID分子诊断的高潜力， 研究，并确定新的治疗目标，以减缓进展，延迟发作，并可能治疗一些 身份证的形式。

Project Summary According to WHO estimates, neurological conditions account for over 6% of the global disease burden. There are more than 600 neurological disorders and cognitive dysfunction, also referred to as intellectual disability (ID), occupies a prominent position in this list. It is manifested by deficits in adaptive behaviors in everyday social and practical skills, which can have a devastating effect on the lives of affected individuals and their families. Due to its high prevalence of 2-3%,2; 3 and the lifetime cost of care per individual in the range of $1-2 million in United Sates,4 ID presents a significant health burden and is a major challenge at the clinical level. Genetic factors are involved in the etiology of 25-50% of ID cases. 2 Genetic and functional studies of the genes and protein determinants of ID have helped to elucidate the molecular pathways of human brain development in health and disease. However the identity of a large number of essential molecular and cellular components remain unknown. The Objective of the proposed research is to identify and characterize genes/proteins essential for autosomal recessive ID (ARID). The rationale is that identification of causative gene variants that lead to ARID and elucidation of the functions of normal genes will be essential for understanding brain function and developing improved diagnostic tools and efficacious preventive and therapeutic agents for neurological disorders in general and ID in particular. The project addresses NIH’s mission to generate basic knowledge that may be translatable to reduce the burden of human diseases. There are 3 aims: 1) Ascertain and clinically phenotype members of extended families segregating ARID; 2) identify new ARID genes and gene products; and 3) determine synaptic functions of prioritized novel ARID genes, by analyzing spatiotemporal expression patterns in mouse brain, synaptic targeting in cultured rat hippocampal neurons, effects on cell morphology and synapse abundance, synaptic transmission and plasticity in neuronal cells by electrophysiology, live-cell imaging, and in utero electroporation assays. The project will advantageously combine human clinical assessment, genetic and functional analyses relevant to brain development and function. Impact: Execution of the proposed studies will generate new knowledge that is clinically relevant, with high potential to impact ID molecular diagnosis, prognoses, and identify novel therapeutics targets to slow progression, delay onset, and possibly treat some forms of ID.