Analysis of pathogenic mosaic mutations in human Amyotrophic Lateral Sclerosis nervous system

人肌萎缩侧索硬化症神经系统致病性嵌合突变分析

• 批准号: 10576017
• 负责人: Michael Anthony Lodato
• 金额: $ 46.06万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-10 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10576017
• 关键词: ALS patients; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Automobile Driving; Autopsy; Blood; Brain; Cell Nucleus; Cells; Clinical; Code; Cortical Dysplasia; DNA; DNA Sequence Alteration; Data; Data Set; Development; Disease; Doctor of Medicine; Doctor of Philosophy; Drug or chemical Tissue Distribution; Embryo; Embryonic Development; Etiology; Exons; Family; Fertilization; Fetal Development; Genes; Genetic; Germ-Line Mutation; Human; Inherited; Investigation; Knowledge; Laboratories; Link; Methods; Microgyria; Mosaicism; Motor Cortex; Motor Neuron Disease; Motor Neurons; Mutate; Mutation; Mutation Analysis; Nerve Degeneration; Nervous system structure; Neuraxis; Neurodegenerative Disorders; Neurologic; Organism; Parents; Pathogenicity; Pathology; Patients; Play; Recording of previous events; Regulatory Element; Role; Sampling; Somatic Mutation; Spinal Cord; Technology; Testing; Therapeutic; Tissues; Untranslated RNA; Variant; amyotrophic lateral sclerosis therapy; autism spectrum disorder; autosomal dominant mutation; base; cohort; deep sequencing; early onset; exome sequencing; experimental study; familial amyotrophic lateral sclerosis; frontier; genome analysis; genome sequencing; hemimegalencephaly; interdisciplinary approach; meetings; nervous system disorder; non-genetic; novel; personalized therapeutic; progenitor; progenitor system; relating to nervous system; risk variant; single cell analysis; single cell sequencing; sporadic amyotrophic lateral sclerosis; targeted sequencing; transcriptome sequencing; whole genome

Summary Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the loss of motor neurons in the spinal cord and brain. While autosomal dominant mutations in several known genes can cause familial ALS, most ALS cases (90-95%) display no family history so are classified as sporadic. Mechanisms driving sporadic ALS are poorly understood, hindering the search for treatments and a cure. Somatic mutations are DNA variants that arise after fertilization and are thus mosaic in the body, and somatic mutations have been shown to be causal in several non-inherited neurological disorders. Our proposal aims to test whether somatic mutations, in ALS risk genes or other genes, in the spinal cord or brain can cause sporadic ALS. To test this hypothesis, we will use an interdisciplinary approach, combining the expertise in the clinical features and genetics of ALS from the laboratory of Robert Brown DPhil., M.D. with expertise in somatic mutations and single-cell analysis in the lab of Michael Lodato, Ph.D. We will analyze somatic mutations in a consortium-generated whole-genome sequencing (WGS) dataset, and analyze somatic mutations in ultra-deep (500x) whole-exome sequencing (WES) data generated in this proposal. These experiments will allow us to study somatic mutations impacting sporadic ALS at all embryonic stages, including early somatic mutations distributed across the body, and late embryonic somatic mutations that might occur in a committed central nervous system progenitor and be restricted to the brain and spinal cord. Our preliminary data suggest that all donors are marked by somatic mutations, some of which generate predicted deleterious changes. If successful, we will open a new frontier in ALS genetics, and define new patient cohorts who are candidates for recently developed, mutation-specific personalized therapeutics.

总结 肌萎缩侧索硬化症（ALS）是一种进行性神经退行性疾病，其特征在于 脊髓和大脑中的运动神经元。虽然几个已知基因中的常染色体显性突变可以 大多数ALS病例（90-95%）没有家族史，因此被归类为散发性。 驱动散发性ALS的机制知之甚少，阻碍了治疗和治愈的研究。 体细胞突变是受精后产生的DNA变体，因此在体内是嵌合的，而体细胞突变是在受精后产生的。 突变已被证明是几种非遗传性神经系统疾病的病因。我们的建议旨在 测试ALS风险基因或其他基因中的体细胞突变，脊髓或大脑中的体细胞突变是否会导致散发性ALS， 人症为了验证这一假设，我们将使用跨学科的方法，结合临床领域的专业知识， ALS的特征和遗传学，M.D.有着身体方面的专业知识 突变和单细胞分析在实验室的迈克尔Lodato，博士我们将在一个 财团产生的全基因组测序（WGS）数据集，并分析超深 （500倍）全外显子组测序（WES）数据。这些实验将使我们能够 研究在所有胚胎阶段影响散发性ALS的体细胞突变，包括早期体细胞突变， 分布在整个身体，和晚期胚胎体细胞突变，可能发生在一个承诺的中央 神经系统祖细胞，并限于大脑和脊髓。我们的初步数据显示， 供体的特征是体细胞突变，其中一些产生了预测的有害变化。如果成功， 我们将在ALS遗传学方面开辟一个新的前沿，并定义新的患者群体， 开发出针对突变的个性化治疗方法。