Severe CMT type 2 with fatal encephalopathy associated with a novel MFN2 splicing mutation.

Mutations in the MFN2 gene, encoding mitofusin2, cause autosomal dominant axonal Charcot-Marie-Tooth type 2 (CMT2A). In this work we studied a sibship with 3 affected and 3 apparently healthy individuals. Sequencing of MFN2 identified a substitution in intron 13 (c.1392 _ 2T_C) in all affected subjects, and also in a 64-year-old sister with no signs of neuropathy. The mutation, affecting the GT donor splice site of intron 13, was not identified in 200 control chromosomes. RT-PCR analysis detected a single transcript corresponding to the wild-type MFN2 mRNA in noncarrier family members, whereas all the subjects harboring the mutation had 4 additional aberrant transcripts. An in vitro splicing assay confirmed the alteration and revealed that the mutation completely abolishes exon 13 correct splicing. The mutant construct showed different splicing patterns in the cell lines, suggesting that the activation of cryptic splice sites may be under control of tissue-specific factors.