title: Novel mitofusin 2 splice-site mutation causes Charcot-Marie-Tooth disease type 2 with prominent sensory dysfunction.
abstract: 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.
authors: University of Turku and Turku University Hospital, Division of Clinical Neurosciences, Turku, Finland. Electronic address: mikmar@utu.fi.
authors: Mika H
authors: MH
authors: Martikainen
authors: University of Oulu and Oulu University Hospital, Department of Clinical Medicine, Neurology, Medical Research Center Oulu, Oulu, Finland.
authors: Laura
authors: L
authors: Kytövuori
authors: University of Oulu and Oulu University Hospital, Department of Clinical Medicine, Neurology, Medical Research Center Oulu, Oulu, Finland.
authors: Kari
authors: K
authors: Majamaa
mesh_terms: D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000503:physiopathology*; D004252:DNA Mutational Analysis; D005190:Family; D005387:Finland; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics*; D009046:Motor Neurons / Q000502:physiology; D009154:Mutation; D010641:Phenotype; D011984:Sensory Receptor Cells / Q000502:physiology; D055815:Young Adult
chemical_list: D024101:Mitochondrial Proteins; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human
keywords: Charcot–Marie–Tooth; Hereditary motor and sensory neuropathy; MFN2; Mutation; Phenotype