Department of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan.
Parkinsonism Relat Disord. 2023 Apr;109:105353. doi: 10.1016/j.parkreldis.2023.105353. Epub 2023 Feb 27.
Mitochondrial membrane protein‒associated neurodegeneration (MPAN) is a rare genetic disease characterized by progressive neurodegeneration with brain iron accumulations combined with neuronal α-synuclein and tau aggregations. Mutations in C19orf12 have been associated with both autosomal recessive and autosomal dominant inheritance patterns of MPAN.
We present clinical features and functional evidence from a Taiwanese family with autosomal dominant MPAN caused by a novel heterozygous frameshift and nonsense mutation in C19orf12, c273_274 insA (p.P92Tfs9). To verify the pathogenicity of the identified variant, we examined the mitochondrial function, morphology, protein aggregation, neuronal apoptosis, and RNA interactome in p.P92Tfs9 mutant knock-in SH-SY5Y cells created with CRISPR-Cas9 technology.
Clinically, the patients with the C19orf12 p.P92Tfs9 mutation presented with generalized dystonia, retrocollis, cerebellar ataxia, and cognitive decline, starting in their mid-20s. The identified novel frameshift mutation is located in the evolutionarily conserved region of the last exon of C19orf12. In vitro studies revealed that the p.P92Tfs9 variant is associated with impaired mitochondrial function, reduced ATP production, aberrant mitochondria interconnectivity and ultrastructure. Increased neuronal α-synuclein and tau aggregations, and apoptosis were observed under conditions of mitochondrial stress. Transcriptomic analysis revealed that the expression of genes in clusters related to mitochondrial fission, lipid metabolism, and iron homeostasis pathways was altered in the C19orf12 p.P92Tfs*9 mutant cells compared to control cells.
Our findings provide clinical, genetic, and mechanistic insight revealing a novel heterozygous C19orf12 frameshift mutation to be a cause of autosomal dominant MPAN, further strengthening the importance of mitochondrial dysfunction in the pathogenesis of MPAN.
线粒体膜蛋白相关神经退行性变（MPAN）是一种罕见的遗传性疾病，其特征是进行性神经退行性变，伴有脑铁蓄积，同时伴有神经元α-突触核蛋白和 tau 聚集。C19orf12 突变与常染色体隐性和常染色体显性遗传模式的 MPAN 有关。
我们介绍了一个台湾家族的临床特征和功能证据，该家族患有常染色体显性 MPAN，由 C19orf12 中的一个新的杂合框移突变和无义突变引起，c273_274 insA（p.P92Tfs9）。为了验证鉴定变异的致病性，我们使用 CRISPR-Cas9 技术在 p.P92Tfs9 突变敲入 SH-SY5Y 细胞中检查了线粒体功能、形态、蛋白质聚集、神经元凋亡和 RNA 相互作用。
临床上，C19orf12 p.P92Tfs9 突变患者表现为全身性肌张力障碍、反颈、小脑共济失调和认知能力下降，始于 20 多岁中期。鉴定出的新型框移突变位于 C19orf12 最后一个外显子的进化保守区域。体外研究表明，p.P92Tfs9 变体与线粒体功能受损、ATP 产生减少、异常的线粒体连接和超微结构有关。在线粒体应激条件下，观察到神经元α-突触核蛋白和 tau 聚集增加和凋亡。转录组分析显示，与线粒体分裂、脂质代谢和铁稳态途径相关的基因簇在 C19orf12 p.P92Tfs*9 突变细胞中的表达与对照细胞相比发生了改变。
我们的研究结果提供了临床、遗传和机制方面的见解，揭示了一种新的杂合 C19orf12 框移突变是常染色体显性 MPAN 的原因，进一步加强了线粒体功能障碍在 MPAN 发病机制中的重要性。
