Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that appears in at least one-third of adult carriers of FMR1 premutation. Several studies have shown that mitochondrial dysfunction may play a role in neurodegenerative disorders. In order to assess whether mitochondrial DNA variants are involved in the risk of developing FXTAS we evaluated the frequency of mitochondrial haplogroups in 132 unrelated Spanish FMR1 premutation carriers. In addition, the entire mitogenome of 26 FMR1 premutation carriers was sequenced using massively parallel sequencing technologies to analyze mitochondrial DNA variants. Statistical analyses reveal a significant difference in the frequency of T haplogroup. Data analysis of mitochondrial DNA sequences evidence an association between FXTAS and the burden of heteroplasmic variants as well as their distribution. Our results suggest that haplogroup T might be a potential protective factor for FXTAS and that FXTAS individuals accumulate higher rates of heteroplasmic variants in compromised regions of the mitochondrial genome. These results may explain, in part, the role of mitochondrial DNA in the development of FXTAS.

中文翻译：

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线粒体 DNA 变异在脆性 X 相关震颤/共济失调综合征发展中的作用

脆性 X 相关震颤/共济失调综合征 (FXTAS) 是一种迟发性神经退行性疾病，至少有三分之一的 FMR1 前突变成年携带者出现。多项研究表明，线粒体功能障碍可能在神经退行性疾病中发挥作用。为了评估线粒体 DNA 变异是否与发展 FXTAS 的风险有关，我们评估了 132 名不相关的西班牙 FMR1 前突变携带者中线粒体单倍群的频率。此外，使用大规模并行测序技术对 26 个 FMR1 前突变携带者的整个有丝分裂基因组进行测序，以分析线粒体 DNA 变体。统计分析揭示了 T 单倍群频率的显着差异。线粒体 DNA 序列的数据分析证明 FXTAS 与异质变异的负担及其分布之间存在关联。我们的结果表明，单倍群 T 可能是 FXTAS 的潜在保护因素，并且 FXTAS 个体在线粒体基因组受损区域中积累了更高的异质变异率。这些结果可以部分解释线粒体 DNA 在 FXTAS 发展中的作用。