PDF(Pubmed)
Abstract：
ALS is a heterogeneous disease in which different factors such as mitochondrial phenotypes act in combination with a genetic predisposition. This study addresses the question of whether homoplasmic (total mitochondrial genome of a sample is affected) and/or heteroplasmic mutations (wildtype and mutant mitochondrial DNA molecules coexist) might play a role in familial ALS. Blood was drawn from familial ALS patients with a possible maternal pattern of inheritance according to their pedigrees, which was compared to blood of ALS patients without maternal association as well as age-matched controls. In two cohorts, we analyzed the mitochondrial genome from whole blood or isolated white blood cells and platelets using a resequencing microarray (Affymetrix MitoChip v2.0) that is able to detect homoplasmic and heteroplasmic mitochondrial DNA mutations and allows the assessment of low-level heteroplasmy.
We identified an increase in homoplasmic ND5 mutations, a subunit of respiratory chain complex I, in whole blood of ALS patients that allowed maternal inheritance. This effect was more pronounced in patients with bulbar onset. Heteroplasmic mutations were significantly increased in different mitochondrial genes in platelets of patients with possible maternal inheritance. No increase of low-level heteroplasmy was found in maternal ALS patients.
Our results indicate a contribution of homoplasmic ND5 mutations to maternally associated ALS with bulbar onset. Therefore, it might be conceivable that specific maternally transmitted rather than randomly acquired mitochondrial DNA mutations might contribute to the disease process. This stands in contrast with observations from Alzheimer\'s and Parkinson\'s diseases showing an age-dependent accumulation of unspecific mutations in mitochondrial DNA.
We identified an increase in homoplasmic ND5 mutations, a subunit of respiratory chain complex I, in whole blood of ALS patients that allowed maternal inheritance. This effect was more pronounced in patients with bulbar onset. Heteroplasmic mutations were significantly increased in different mitochondrial genes in platelets of patients with possible maternal inheritance. No increase of low-level heteroplasmy was found in maternal ALS patients.
Our results indicate a contribution of homoplasmic ND5 mutations to maternally associated ALS with bulbar onset. Therefore, it might be conceivable that specific maternally transmitted rather than randomly acquired mitochondrial DNA mutations might contribute to the disease process. This stands in contrast with observations from Alzheimer\'s and Parkinson\'s diseases showing an age-dependent accumulation of unspecific mutations in mitochondrial DNA.
摘要：
ALS是一种异质性疾病，其中线粒体表型等不同因素与遗传易感性相结合。这项研究解决了同质（样品的总线粒体基因组受到影响）和/或异质突变（野生型和突变的线粒体DNA分子共存）是否可能在家族性ALS中起作用的问题。从家族性ALS患者中抽取血液，根据他们的家谱可能具有母体遗传模式，将其与没有母亲关联的ALS患者以及年龄匹配的对照组的血液进行比较。在两个队列中，我们使用重测序微阵列(AffymetrixMitoChipv2.0)分析了来自全血或分离的白细胞和血小板的线粒体基因组,该微阵列能够检测同质和异质线粒体DNA突变,并允许评估低水平的异质性.
我们发现同质ND5突变增加，呼吸链复合体I的一个亚基，允许母体遗传的ALS患者的全血中。这种效果在球起病的患者中更为明显。在可能具有母体遗传的患者的血小板中，不同线粒体基因的异质突变显着增加。在母体ALS患者中没有发现低水平的异质体增加。
我们的结果表明同质ND5突变对与延髓发病的母系相关ALS的贡献。因此,可以想象,特定的母体传播而不是随机获得的线粒体DNA突变可能有助于疾病过程.这与阿尔茨海默氏症和帕金森氏症的观察结果相反，这些疾病显示线粒体DNA中非特异性突变的年龄依赖性积累。
我们发现同质ND5突变增加，呼吸链复合体I的一个亚基，允许母体遗传的ALS患者的全血中。这种效果在球起病的患者中更为明显。在可能具有母体遗传的患者的血小板中，不同线粒体基因的异质突变显着增加。在母体ALS患者中没有发现低水平的异质体增加。
我们的结果表明同质ND5突变对与延髓发病的母系相关ALS的贡献。因此,可以想象,特定的母体传播而不是随机获得的线粒体DNA突变可能有助于疾病过程.这与阿尔茨海默氏症和帕金森氏症的观察结果相反，这些疾病显示线粒体DNA中非特异性突变的年龄依赖性积累。
