Mice Hemizygous for a Pathogenic Mitofusin-2 Allele Exhibit Hind Limb/Foot Gait Deficits and Phenotypic Perturbations in Nerve and Muscle

PLoS One. 2016 Dec 1;11(12):e0167573. doi: 10.1371/journal.pone.0167573. eCollection 2016.


Charcot-Marie-Tooth disease type 2A (CMT2A), the most common axonal form of hereditary sensory motor neuropathy, is caused by mutations of mitofusin-2 (MFN2). Mitofusin-2 is a GTPase required for fusion of mitochondrial outer membranes, repair of damaged mitochondria, efficient mitochondrial energetics, regulation of mitochondrial-endoplasmic reticulum calcium coupling and axonal transport of mitochondria. We knocked T105M MFN2 preceded by a loxP-flanked STOP sequence into the mouse Rosa26 locus to permit cell type-specific expression of this pathogenic allele. Crossing these mice with nestin-Cre transgenic mice elicited T105M MFN2 expression in neuroectoderm, and resulted in diminished numbers of mitochondria in peripheral nerve axons, an alteration in skeletal muscle fiber type distribution, and a gait abnormality.

MeSH terms

  • Alleles*
  • Amino Acid Substitution
  • Animals
  • Axonal Transport
  • Charcot-Marie-Tooth Disease / genetics*
  • Charcot-Marie-Tooth Disease / metabolism
  • Charcot-Marie-Tooth Disease / pathology
  • Disease Models, Animal
  • Embryo, Mammalian
  • GTP Phosphohydrolases / deficiency
  • GTP Phosphohydrolases / genetics*
  • Gait
  • Gene Expression Regulation
  • Hemizygote*
  • Hindlimb / pathology
  • Humans
  • Integrases / genetics
  • Integrases / metabolism
  • Mice
  • Mice, Transgenic
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Muscle Fibers, Skeletal / metabolism*
  • Muscle Fibers, Skeletal / pathology
  • Nestin / genetics
  • Nestin / metabolism
  • Neural Plate / metabolism
  • Neural Plate / pathology
  • Peripheral Nerves / metabolism*
  • Peripheral Nerves / pathology
  • Phenotype
  • RNA, Untranslated / genetics
  • RNA, Untranslated / metabolism


  • Gt(ROSA)26Sor non-coding RNA, mouse
  • Nes protein, mouse
  • Nestin
  • RNA, Untranslated
  • Cre recombinase
  • Integrases
  • GTP Phosphohydrolases
  • Mfn2 protein, mouse

Grant support

This work was funded by Shriners Hospitals for Children and by a pilot grant from the Hereditary Neuropathy Foundation.