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多种神经障碍和认知功能障碍，也称为智力残疾(ID)， 在这份名单中占据着突出的位置。它表现为日常社会和生活中适应行为的缺陷 实用技能，这可能对受影响个人及其家人的生活产生破坏性影响。由于 在美国，它的高患病率为2-3%，2；3，每个人一生的护理费用在100-200万美元之间 Sates，4ID是一个重大的健康负担，在临床层面上是一个主要的挑战。遗传因素有 涉及25%-50%的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健康和健康人脑发育的分子途径 疾病。然而，大量重要的分子和细胞成分的特性仍然存在 未知。这项拟议的研究的目标是识别和表征基因/蛋白质 常染色体隐性遗传ID(ADRID)。其基本原理是识别导致干旱的致病基因变异 阐明正常基因的功能将对了解大脑功能和发育至关重要。 改进的诊断工具和有效的神经疾病预防和治疗药物 尤其是ID。该项目致力于NIH产生可能可翻译的基本知识的使命 以减轻人类疾病的负担。有三个目的：1)确定和临床表型成员 大家族分离干旱；2)识别新的干旱基因和基因产物；以及3)确定突触 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突触靶向及其对细胞形态和突触丰度的影响 神经细胞中突触传递和可塑性的电生理学、活细胞成像和宫内研究 电穿孔分析。该项目将有利地结合人类临床评估、遗传学和 与大脑发育和功能相关的功能分析。影响：执行拟议的研究将 产生与临床相关的、具有影响ID分子诊断的高潜力的新知识， 预测预后，并确定新的治疗靶点以减缓进展，延迟发病，并可能治疗某些疾病 身份证的格式。

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.