Using LIS1 missense mutations to probe dynein regulatory mechanisms

利用 LIS1 错义突变探测动力蛋白调节机制

• 批准号: 10544530
• 负责人: DEANNA S SMITH
• 金额: $ 21.91万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10544530
• 关键词: ASD patient; Address; Adult; Alzheimer' s Disease; Amino Acid Substitution; Amyotrophic Lateral Sclerosis; Axon; Axonal Transport; Benign; Binding; Biological Assay; Brain Diseases; COS-7 Cell; Categories; Cell physiology; Cessation of life; Childhood; ClinVar; Complex; Cortical Malformation; Cytoplasm; Data Set; Databases; Degenerative Disorder; Development; Developmental Brain Malformation; Disease; Dynein ATPase; Genes; Impaired cognition; Individual; LIS1 protein; Late-Onset Disorder; Link; Measures; Microtubules; Mild Dysplasia; Missense Mutation; Motor; Motor Activity; Mutation; Nervous System; Neurologic; Neurons; Nomenclature; Organelles; Pathway interactions; Patients; Phenotype; Proteins; Regulation; Reporting; Role; Seizures; Severity of illness; Tertiary Protein Structure; Testing; autism spectrum disorder; autosomal dominant mutation; boys; dominant genetic mutation; genetic regulatory protein; interest; lissencephaly; migration; motor impairment; mutant; nervous system disorder; novel; protein function

SUMMARY: It is becoming clear that genes associated with different neurological diseases are shared across disorders and converge on common functional pathways. For example, pathways that control the microtubule motor cytoplasmic dynein 1 (hereafter referred to as “dynein”) are perturbed in multiple disorders from cortical malformations to ALS and other degenerative diseases [1]. This motor is indispensable for a wide range of cellular processes in the developing and mature nervous system [2]. Our group is interested in the dynein regulatory protein, LIS1. As a vital dynein regulator, it is surprising that PAFAH1B1 mutations have not been found in other neurological diseases. We are currently studying a novel LIS1 missense mutation (K351R) in a boy with Autism Spectrum Disorder (ASD), supporting the possibility that some LIS1 mutations can lead to less severe disease. Most, if not all, LIS1 roles are related to dynein regulation. Around 20 genes encoding LIS1-interacting or dynein regulatory proteins that have potential autism spectrum disorder (ASD)-linked mutations, so perturbations in dynein regulation could predispose to ASD. There are other missense mutations that could lead to partially functional proteins in several online databases. In this R21 exploratory project we will test the hypothesis that individual LIS1 missense mutations will disrupt specific LIS1 interactions, thereby differentially regulating dynein and impacting disease severity. We will determine how each mutation impacts critical LIS1 interactions, and how they impact LIS1’s ability to regulate dynein. This study will be the first to systematically dissect the impact of LIS1 missense mutations in different domains of the protein on dynein function, and to correlate changes in dynein function with disease severity. As neurons are uniquely sensitive to reduced LIS1 expression they might be negatively impacted even by small changes in LIS1 that subtly alter dynein function. Because LIS1 is critical in both the developing and adult nervous system, our studies could provide a springboard for understanding dynein deregulation across a wide range of neurological disorders, including ASD and later onset disorders such as Alzheimer’s Disease and Amyotrophic Lateral Sclerosis.

摘要：越来越清楚的是，与不同神经系统疾病相关的基因是共享的 并汇聚在共同的功能通路上。例如，控制神经元的通路 微管运动细胞质动力蛋白1（下文称为“动力蛋白”）在多个细胞中被扰动， 从皮质畸形到ALS和其他退行性疾病[1]。该马达 在发育和成熟的神经系统中，它对广泛的细胞过程是必不可少的[2]。 我们的团队对动力蛋白调节蛋白LIS1感兴趣。作为一种重要的动力蛋白调节剂， PAFAH1B1突变在其他神经系统疾病中尚未发现。我们目前正在 研究一名患有自闭症谱系障碍（ASD）的男孩的新型LIS1错义突变（K351R）， 支持了某些LIS1突变可能导致不太严重的疾病的可能性。大多数，如果不是全部，LIS1 作用与动力蛋白调节有关。大约20个基因编码LIS1相互作用或动力蛋白调节 具有潜在自闭症谱系障碍（ASD）相关突变的蛋白质，因此 动力蛋白调节可能易患ASD。还有其他的错义突变可能导致 部分功能蛋白质在几个在线数据库。在这个R21探索性项目中，我们将测试 假设单个LIS1错义突变会破坏特定的LIS1相互作用， 差异调节动力蛋白并影响疾病严重程度。我们将确定每个突变 影响关键的LIS1相互作用，以及它们如何影响LIS1调节动力蛋白的能力。 这项研究将是第一个系统地剖析LIS1错义突变在不同基因型中的影响。 蛋白质结构域对动力蛋白功能的影响，并将动力蛋白功能的变化与疾病相关 严重性。由于神经元对LIS1表达的减少特别敏感，因此它们可能是负性的。 甚至受到LIS1微小变化的影响，这些变化微妙地改变了动力蛋白的功能。因为LIS1在这两个方面都很关键， 我们的研究可以提供一个跳板， 动力蛋白失调在广泛的神经系统疾病，包括ASD和迟发性 阿尔茨海默病和肌萎缩性侧索硬化症。