A Mitochondrial Etiology of Autism

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(ASD)病因学中的一个重要因素的假设。线粒体在细胞和组织的功能中起着四个核心作用：它们提供大部分能量，产生大量的活性氧物种(ROS)，缓冲细胞内的钙，以及基于线粒体的状态调节细胞死亡。线粒体基因组被认为包含1500个核DNA(NDNA)基因和37个线粒体DNA(MtDNA)基因。ASD淋巴母细胞系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)，其中许多CNV位于线粒体基因的内部。更多的分析揭示了线粒体DNA的改变。由于部分线粒体氧化磷酸化(OXPHOS)缺陷足以导致神经系统疾病，这些结果表明线粒体功能障碍可能占ASD的很大比例。为了进一步验证这一假说，我们建议：(1)扩大我们对影响ASD淋巴母细胞系线粒体基因的nDNA CNV的搜索，(2)分析ASD淋巴母细胞中mtDNA的变异，(3)利用线粒体生化和体细胞遗传学来证明淋巴母细胞表现出nDNA和/或mtDNA变异体预测的线粒体缺陷，以及(4)使用肌肉和大脑的无创性磁共振光谱(MRS)、微量有机呼气分析(MOBA)和肌肉的漫反射光学光谱(DOS)来证实选定突变患者中线粒体缺陷的存在。证明一部分ASD患者存在线粒体缺陷将为这类ASD的治疗提供新的方法。 公共卫生相关性：为了确定自闭症谱系(ASD)疾病的子集是否由线粒体功能障碍引起，我们建议调查患者淋巴母细胞系，以寻找那些携带核DNA(NDNA)拷贝数变异(CNV)或线粒体DNA(MtDNA)突变改变线粒体基因的细胞株。来自突变患者的细胞系将被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。

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.