Barsa Chloe, Perrin Julian, David Claudine, Mourier Arnaud, Rojo Manuel
CNRS, IBGC, UMR 5095, Institut de Biochimie et Génétique Cellulaires (IBGC), Université de Bordeaux, 33000, Bordeaux, France.
Sci Rep. 2025 Mar 22;15(1):9971. doi: 10.1038/s41598-025-93702-1.
Charcot-Marie-Tooth Disease (CMT) is an inherited peripheral neuropathy with two main forms: demyelinating CMT1 and axonal CMT2. The most frequent subtype of CMT2 (CMT2A) is linked to mutations of MFN2, encoding a ubiquitously expressed GTP-binding protein anchored to the mitochondrial outer membrane and essential for mitochondrial fusion. The use of Next-Generation Sequencing has led to the identification of increasing numbers of MFN2 variants, yet many of them remain of unknown significance, depriving patients of a clear diagnosis. In this work, we establish a cellular assay allowing to assess the impact of 12 known MFN2 variants linked to CMT2A on mitochondrial fusion. The functional analysis revealed that out of the 12 selected MFN2 mutations, only six exhibited reduced fusion activity. The classification of MFN2 variants according to the results of the functional assay revealed a correlation between the fusion capacity, the age at onset of CMT2A and computational variant effect predictions relying on the analysis of the protein sequence. The functional assay and the results obtained will assist and improve the classification of novel MFN2 variants identified in patients.
夏科-马里-图斯病（CMT）是一种遗传性周围神经病，主要有两种类型：脱髓鞘型CMT1和轴索性CMT2。CMT2最常见的亚型（CMT2A）与MFN2基因突变有关，MFN2编码一种普遍表达的GTP结合蛋白，该蛋白锚定在线粒体外膜上，对线粒体融合至关重要。新一代测序技术的应用使得越来越多与CMT2A相关的MFN2变体被识别出来，但其中许多变体的意义仍不明确，这使得患者无法得到明确诊断。在这项研究中，我们建立了一种细胞检测方法，用于评估12种已知的与CMT2A相关的MFN2变体对线粒体融合的影响。功能分析表明，在所选的12种MFN2突变中，只有6种表现出融合活性降低。根据功能检测结果对MFN2变体进行分类，结果显示融合能力、CMT2A发病年龄与基于蛋白质序列分析的计算变体效应预测之间存在相关性。该功能检测及所获得的结果将有助于并改进对患者中鉴定出的新型MFN2变体的分类。
