A Mitochondrial Etiology of Autism

描述（由申请人提供）：我们提议验证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功能中发挥着四个核心作用：它们提供大部分能量，产生大部分活性氧（ROS），缓冲胞质钙离子，并根据线粒体状态调节细胞死亡。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。一项对ASD淋巴母细胞样细胞系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（CNVs），其中许多CNVs位于线粒体基因内部。进一步的分析揭示了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，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设，我们提出：(1)扩大对影响ASD淋巴母细胞样细胞系线粒体基因的nDNA CNVs的研究；(2)分析ASD淋巴母细胞mtDNA变异；(3)利用线粒体生物化学和体细胞遗传学证明淋巴母细胞表现出由nDNA和/或mtDNA变异预测的线粒体缺陷；(4)利用肌肉和大脑的非侵入性磁共振波谱（MRS）证实在选择的突变患者中存在线粒体缺陷。微生物呼吸分析（MOBA）和肌肉漫射光谱学（DOS）。证明一小部分ASD患者存在线粒体缺陷将为治疗这类ASD提供新的方法。

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.