Molecular Biology Unit, Mossakowski Medical Research Centre, PAS, 02-106, Warsaw, 5 Pawińskiego St, Poland.
Faculty of Physics, University of Warsaw, 02-093, Warsaw, 5 Pasteura St, Poland.
Sci Rep. 2018 Nov 15;8(1):16900. doi: 10.1038/s41598-018-35133-9.
Charcot-Marie-Tooth disease type 2A (CMT2A) is an autosomal dominant neuropathy caused by mutations in the mitofusin 2 gene (MFN2). More than 100 MFN2 gene mutations have been reported so far, with majority located within the GTPase domain encoding region. These domain-specific mutations present wide range of symptoms with differences associated with distinct amino acid substitutions in the same position. Due to the lack of conclusive phenotype-genotype correlation the predictive value of genetic results remains still limited. We have explored whether changes in the protein structure caused by MFN2 mutations can help to explain diseases phenotypes. Using a stable protein model, we evaluated the effect of 26 substitutions on the MFN2 structure and predicted the molecular consequences of such alterations. The observed changes were correlated with clinical features associated with a given mutation. Of all tested mutations positive correlation of molecular modelling with the clinical features reached 73%. Our analysis revealed that molecular modelling of mitofusin 2 mutations is a powerful tool, which predicts associated pathogenic impacts and that these correlate with clinical outcomes. This approach may aid an early diagnosis and prediction of symptoms severity in CMT2A patients.
腓骨肌萎缩症 2A 型（CMT2A）是一种常染色体显性遗传性周围神经病，由线粒体融合蛋白 2 基因（MFN2）突变引起。迄今为止，已经报道了超过 100 种 MFN2 基因突变，其中大多数位于 GTPase 结构域编码区。这些特定结构域的突变表现出广泛的症状差异，与同一位置的不同氨基酸取代有关。由于缺乏明确的表型-基因型相关性，遗传结果的预测价值仍然有限。我们探讨了 MFN2 突变引起的蛋白质结构变化是否有助于解释疾病表型。我们使用稳定的蛋白质模型，评估了 26 种取代对 MFN2 结构的影响，并预测了这些改变的分子后果。观察到的变化与特定突变相关的临床特征相关。在所有测试的突变中，分子建模与临床特征的正相关达到 73%。我们的分析表明，线粒体融合蛋白 2 突变的分子建模是一种强大的工具，可以预测相关的致病影响，并且这些影响与临床结果相关。这种方法可以帮助 CMT2A 患者进行早期诊断和症状严重程度的预测。
