Novel mitofusin 2 splice-site mutation causes Charcot-Marie-Tooth disease type 2 with prominent sensory dysfunction.

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.