Next-generation sequencing of the whole mitochondrial genome identifies functionally deleterious mutations in patients with multiple sclerosis

The study analyzed the whole mitochondrial genome, using next-generation sequencing, from Saudi subjects with relapsing-remitting multiple sclerosis (MS) and healthy controls to identify mtDNA disease-related mutations/variants. A large number of variants were detected in the D-loop and coding genes of mtDNA. While distinct unique variants were only present in the patients or only occur in the controls, a number of common variants were shared among the two groups. The prevalence of some common variants differed significantly between patients and controls (P<0.05), and could be implicated in susceptibility to MS. Of the unique variants only present in the patients, 34 were categorized as missense mutations, located in different mtDNA-encoded genes. Seven of these mutations were not previously reported in MS, and predicted to be deleterious with significant impacts on the functions and structures of encoded-proteins and may play a role in the pathogenesis of MS. Notably some patients harboured multiple mutations while other patients carried the same mutations. Our study is the first to sequence the entire mitochondrial genome in patients with MS in an Arab population. The results expanded the mutational spectrum of mtDNA variants in MS and highlighted the efficiency of NGS in population-specific mtDNA variant discovery.

本研究针对沙特阿拉伯籍复发缓解型多发性硬化（multiple sclerosis, MS）患者与健康对照人群，采用二代测序（next-generation sequencing, NGS）技术对其全线粒体基因组进行分析，以鉴定与线粒体DNA（mitochondrial DNA, mtDNA）疾病相关的突变/变异。研究在mtDNA的D环与编码基因区域检测到大量变异。尽管存在仅在患者中独有、或仅在对照人群中出现的特异性变异，但两组人群共享了多种常见变异。部分常见变异的携带频率在患者与对照人群间存在显著差异（P<0.05），或与MS易感性相关。在仅存在于患者中的独有变异中，有34个被归类为错义突变（missense mutations），分布于不同的mtDNA编码基因中。其中7个突变此前未在MS相关研究中被报道，经预测具有有害性，可对编码蛋白的功能与结构产生显著影响，或参与MS的发病机制。值得注意的是，部分患者携带多种突变，而另有部分患者携带相同突变。本研究是首个在阿拉伯人群中对MS患者开展全线粒体基因组测序的研究。研究结果拓展了MS中mtDNA变异的突变谱，并凸显了二代测序在人群特异性mtDNA变异发掘中的高效性。