A Mitochondrial Etiology of Autism

描述（由申请人提供）：我们提出测试线粒体功能障碍是自闭症谱系障碍（ASD）病因学中的重要因素的假设。线粒体在细胞和组织功能中发挥四个中心作用：它们提供大部分能量，产生大量活性氧（ROS），缓冲细胞溶质Ca++，并基于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。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线粒体基因的多拷贝数变体（CNV），许多CNV在线粒体基因内部。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的显着比例。为了进一步验证这一假设，我们建议：（1）扩大我们对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淋巴母细胞中的mtDNA变异，（3）使用线粒体生物化学和体细胞遗传学来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，和（4）使用肌肉和脑的非侵入性磁共振波谱（MRS）、微有机呼吸分析（MOBA）和肌肉的扩散光学波谱（DOS）确认所选突变患者中线粒体缺陷的存在。证明ASD患者的一个子集具有线粒体缺陷将为治疗这类ASD提出新的方法。 公共卫生相关性：为了确定自闭症谱系（ASD）疾病的一个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样细胞系中携带核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。将检测来自突变患者的细胞系的预期线粒体功能。如果发现线粒体缺陷，将使用非侵入性生物物理和生物化学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.