Abstract
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
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Alleles*
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Amino Acid Substitution
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Animals
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Axonal Transport
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Charcot-Marie-Tooth Disease / genetics*
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Charcot-Marie-Tooth Disease / metabolism
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Charcot-Marie-Tooth Disease / pathology
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Disease Models, Animal
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Embryo, Mammalian
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GTP Phosphohydrolases / deficiency
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GTP Phosphohydrolases / genetics*
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Gait
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Gene Expression Regulation
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Hemizygote*
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Hindlimb / pathology
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Humans
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Integrases / genetics
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Integrases / metabolism
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Mice
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Mice, Transgenic
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Mitochondria / metabolism
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Mitochondria / pathology
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Muscle Fibers, Skeletal / metabolism*
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Muscle Fibers, Skeletal / pathology
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Nestin / genetics
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Nestin / metabolism
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Neural Plate / metabolism
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Neural Plate / pathology
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Peripheral Nerves / metabolism*
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Peripheral Nerves / pathology
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Phenotype
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RNA, Untranslated / genetics
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RNA, Untranslated / metabolism
Substances
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Gt(ROSA)26Sor non-coding RNA, mouse
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Nes protein, mouse
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Nestin
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RNA, Untranslated
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Cre recombinase
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Integrases
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GTP Phosphohydrolases
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Mfn2 protein, mouse
Grant support
This work was funded by Shriners Hospitals for Children and by a pilot grant from the Hereditary Neuropathy Foundation.