Martikainen Mika H, Kytövuori Laura, Majamaa Kari
University of Turku and Turku University Hospital, Division of Clinical Neurosciences, Turku, Finland.
University of Oulu and Oulu University Hospital, Department of Clinical Medicine, Neurology, Medical Research Center Oulu, Oulu, Finland.
Neuromuscul Disord. 2014 Apr;24(4):360-4. doi: 10.1016/j.nmd.2014.01.007. Epub 2014 Jan 27.
MFN2 mutations are a major cause of the axonal form of Charcot-Marie-Tooth disease (CMT2). MFN2 encodes mitofusin 2, a mitochondrial fusion protein that is critical for mitochondrial DNA integrity and function. Here we describe CMT2 in a Finnish man and his son, with disease onset in young adulthood, slow progression, and prominent sensory as well as autonomic dysfunction. Molecular analysis revealed in both subjects a previously unreported heterozygous MFN2 mutation c.708G>A that is predicted to abolish a donor splice site for exon 7 of the MFN2 gene. An incorrectly spliced transcript without exon 7 was detected in RT-PCR analysis. The lack of exon 7 creates frameshift and, consequently, premature termination within exon 8. We demonstrated the presence of the aberrant mRNA suggesting either dominant-negative or toxic gain-of-function effect of the heterozygous c.708G>A mutation. This novel mutation adds to the few previously reported pathogenic MFN2 splice site mutations causing CMT2.
MFN2突变是遗传性运动感觉神经病2型（CMT2）轴索性病变的主要病因。MFN2编码线粒体融合蛋白2，该蛋白对线粒体DNA的完整性和功能至关重要。本文描述了一名芬兰男子及其儿子患CMT2的情况，他们在成年早期发病，病情进展缓慢，伴有明显的感觉及自主神经功能障碍。分子分析显示，两名患者均存在一个此前未报道的杂合MFN2突变c.708G>A，预计该突变会消除MFN2基因第7外显子的供体剪接位点。逆转录聚合酶链反应（RT-PCR）分析检测到一个不含第7外显子的错误剪接转录本。第7外显子的缺失导致移码，进而在第8外显子内出现提前终止。我们证实了异常mRNA的存在，提示杂合c.708G>A突变具有显性负性或毒性功能获得效应。这一新突变补充了此前报道的少数导致CMT2的致病性MFN2剪接位点突变。
