A novel variant in MFN2 linked to a lethal disorder of neonatal onset

Pathogenic variants in the mitochondrial fusion protein Mitofusin2 typically cause axonal Charcot-Marie-Tooth disease type 2A (CMT2A), a progressively degenerative peripheral neuropathy. Here, we present two siblings with a lethal disorder of neonatal onset who carried a novel homozygous MFN2 variant R334K, which was predicted to be likely pathogenic. Given the severe clinical presentation, which is atypical of MFN2 variants, further functional investigations were warranted to confirm the pathogenicity of the R334K variant. Characterization of patient fibroblasts showed severe disruptions all MFN2-related functions that were assayed, including mitochondrial fragmentation, altered mito-ER contacts, decreased mtDNA copy number and size, increased abundance of cellular lipid droplets, and reduced mitochondrial respiration. We also observed reduced Complex I activity, which is noted in cells lacking MFN2, but is not typical of pathogenic MFN2 variants that cause CMT2A. Notably, re-expression of MFN2 R334K in MFN2 knockout cells was unable to rescue mitochondrial fragmentation and the Complex I deficiencies, confirming that the R334K variant is causative of these cellular phenotypes. Furthermore, disease modelling in Drosophila melanogaster demonstrated functional deficiencies of the R334K variant in vivo. Together, these findings confirm that the MFN2 R334K is a novel pathogenic variant causing severe fatal neonatal disease patient pathology. Finally, we show that pharmacological activation of the integrated stress response rescues defects caused by MFN2 R334K, offering a potential therapeutic avenue for MFN2 pathology.