A Mitochondrial Etiology of Autism

自闭症的线粒体病因学

基本信息

批准号：
7843063
负责人：
Douglas C Wallace
金额：
$ 59.79万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7843063
关键词：
Accounting Adaptive Behaviors Affect Amino Acids Autistic Disorder Biochemical Biochemistry Blood Brain Breath Tests Buffers Calcium Carnitine Cell Death Cell Line Cells Collection DNA DNA Sequence DNA analysis DNA copy number Defect Detection Diagnosis Diagnostic Diffuse Disease Enzymes Etiology Exhibits Family history of Functional disorder Gene Expression Gene Mutation Gene Rearrangement Genes Genetic Genetic Heterogeneity Genetic Polymorphism Haplogroup Human Genome Language Link Location Magnetic Resonance Spectroscopy Mitochondria Mitochondrial DNA Molecular Molecular Analysis Muscle Mutation Neurologic Nuclear Optics Oxidative Phosphorylation Patients Physiological Play Production Reactive Oxygen Species Research Role Screening procedure Somatic Cell Genetics Southern Blotting Spectrum Analysis Structural Genes Surveys Symptoms Synapses Testing Tissues Universities Urine Variant Vertebral column autism spectrum disorder base comparative genomic hybridization genetic resource genome sequencing lymphoblast lymphoblastoid cell line mitochondrial DNA mutation mitochondrial dysfunction mitochondrial genome mutant nervous system disorder novel strategies organic acid patient registry proband programs public health relevance synaptogenesis tool

项目摘要

DESCRIPTION (provided by applicant): We propose to test the hypothesis that mitochondrial dysfunction is an important factor in the etiology of autism spectrum disorders (ASD). The mitochondria play four central roles in cell and tissue function: they provide most of the energy, generate much of the reactive oxygen species (ROS), buffer cytosolic Ca++, and regulate cell death based on mitochondrial status. The mitochondrial genome is thought to encompass 1500 nuclear DNA (nDNA) genes and 37 mitochondrial DNA (mtDNA) genes. A comparative genomic hybridization (CGH) analysis of ASD lymphoblastoid cell line DNAs has revealed multiple copy number variants (CNVs) that impact nDNA mitochondrial genes, many CNVs being internal to the mitochondrial genes. Additional analyses have revealed mtDNA alterations. Since a partial mitochondrial oxidative phosphorylation (OXPHOS) defect is sufficient to generate neurological disease, these results suggest that mitochondrial dysfunction could account for a significant proportion of ASD. To further test this hypothesis we propose to: (1) expand our search for nDNA CNVs affecting mitochondrial genes in ASD lymphoblastoid cell lines, (2) analyze mtDNA variation in the ASD lymphoblasts, (3) use mitochondrial biochemistry and somatic cell genetics to demonstrate that the lymphoblasts manifest the mitochondrial defect predicted by the nDNA and/or mtDNA variants, and (4) confirm the presence of mitochondrial defects in selected mutant patients using non-invasive magnetic resonance spectroscopy (MRS) of muscle and brain, micro-organic breath analysis (MOBA), and the diffuse optical spectroscopy (DOS) of muscle. Demonstration that a subset of ASD patients harbor mitochondrial defects would suggest new approaches for the treatment of this class of ASD. PUBLIC HEALTH RELEVANCE: To determine if a subset of autism spectrum (ASD) disease is caused by mitochondrial dysfunction, we propose to survey patient lymphoblastoid cell lines for those harboring nuclear DNA (nDNA) copy number variants (CNVs) or mitochondrial DNA (mtDNA) mutations that alter mitochondrial genes. Cell lines from the mutant patients will be tested for the expected mitochondrial function. If mitochondrial defects are found, selected patients will be tested using non-invasive biophysical and biochemical tools to determine if they manifest a functional mitochondrial defect.

描述（由申请人提供）：我们建议测试线粒体功能障碍是自闭症谱系障碍病因（ASD）的重要因素。线粒体在细胞和组织功能中起着四个核心作用：它们提供大部分能量，产生大部分活性氧（ROS），缓冲液胞质CA ++，并根据线粒体状态调节细胞死亡。线粒体基因组被认为包括1500个核DNA（NDNA）基因和37个线粒体DNA（mtDNA）基因。 ASD淋巴细胞细胞系DNA的比较基因组杂交（CGH）分析揭示了影响NDNA线粒体基因的多个拷贝数变异（CNV），许多CNV是线粒体基因内部的许多CNV。其他分析显示了mtDNA的改变。由于部分线粒体氧化磷酸化（OXPHOS）缺陷足以产生神经系统疾病，因此这些结果表明线粒体功能障碍可以占ASD的很大比例。为了进一步检验这一假设，我们提出：（1）扩展我们对ASD淋巴母细胞系中影响线粒体基因的NDNA CNV的搜索，（2）分析ASD淋巴细胞中的mtDNA变异，（3）使用线粒体生物学细胞和躯体遗传学的示出的lym谱，以表现出lymtate suptials cypers cypers suptial suptial suptial cypers cypers cypers cypers cypers cypers cypers cypers cypers suptirate Motters Mottirate Motirate Motters Mottirate Mottort s lympoctots coptrict coptial sister。通过NDNA和/或mtDNA变体预测，（4）使用非侵入性磁共振光谱（MRS），微有机呼吸分析（MOBA）（MOBA）以及肌肉的差异光谱（DOS）证实了所选突变患者的线粒体缺陷。证明了一部分ASD患者含有线粒体缺陷的子集将提出治疗此类ASD的新方法。公共卫生相关性：确定自闭症谱系（ASD）疾病的子集是否是由线粒体功能障碍引起的，我们建议调查具有核DNA（NDNA）拷贝数变体（CNVS）的患者淋巴母细胞系（MTDNA）或线粒体DNA（mTDNA）替代MiTocoChtrial contrial cenes。突变患者的细胞系将测试预期的线粒体功能。如果发现线粒体缺陷，将使用非侵入性生物物理和生化工具对选定的患者进行测试，以确定他们是否表现出功能性线粒体缺陷。