Recessive axonal Charcot-Marie-Tooth disease due to compound heterozygous mitofusin 2 mutations

Polke, James M.; Laurá, Matilde; Pareyson, Davide; Taroni, Franco; Milani, Monica; Bergamin, Giorgia; Gibbons, V.S.; Houlden, Henry; Chamley, S.C.; Blake, Julian; DeVile, Catherine; Sandford, Richard; Sweeney, Mary G.; Davis, Mary B.; Reilly, Mary M.

doi:10.1212/wnl.0b013e3182242d4d

Cited by 71 publications

(58 citation statements)

References 14 publications

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“…Toxic gain-of-function, rather than haploinsufficiency, may be responsible for dominant inheritance in CMT2A [8–9]. In support of this hypothesis, deletion of one MFN2 allele in mice is asymptomatic, as are truncating MFN2 mutations in humans, unless inherited in conjunction with an additional mutation in MFN2 or another CMT-associated allele [10–11]. …”

Section: Introductionmentioning

confidence: 99%

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

Bannerman

Burns

et al. 2016

PLoS ONE

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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.

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Section: Introductionmentioning

confidence: 99%

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

Bannerman

Burns

et al. 2016

PLoS ONE

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“…On the other hand, gain of function experiments in mice overexpressing a CMT-linked mutant MFN2 allele, demonstrated that this was sufficient to induce a specific neurological phenotype [7]. Despite this, several CMT patients with compound heterozygote MFN2 mutations have been reported, and these all manifested as recessively inherited CMT2A [8]. Thus it is feasible that mutant MFN2 can cause CMT in both a dominant and a recessive fashion, depending on the specific genetic defect.…”

Section: Introductionmentioning

confidence: 99%

Axonal Transport Defects in a Mitofusin 2 Loss of Function Model of Charcot-Marie-Tooth Disease in Zebrafish

et al. 2013

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Charcot-Marie-Tooth disease (CMT) represents a group of neurodegenerative disorders typically characterised by demyelination (CMT1) or distal axon degeneration (CMT2) of motor and sensory neurons. The majority of CMT2 cases are caused by mutations in mitofusin 2 (MFN2); an essential gene encoding a protein responsible for fusion of the mitochondrial outer membrane. The mechanism of action of MFN2 mutations is still not fully resolved. To investigate a role for loss of Mfn2 function in disease we investigated an ENU-induced nonsense mutation in zebrafish MFN2 and characterised the phenotype of these fish at the whole organism, pathological, and subcellular level. We show that unlike mice, loss of MFN2 function in zebrafish leads to an adult onset, progressive phenotype with predominant symptoms of motor dysfunction similar to CMT2. Mutant zebrafish show progressive loss of swimming associated with alterations at the neuro-muscular junction. At the cellular level, we provide direct evidence that mitochondrial transport along axons is perturbed in Mfn2 mutant zebrafish, suggesting that this is a key mechanism of disease in CMT. The progressive phenotype and pathology suggest that zebrafish will be useful for further investigating the disease mechanism and potential treatment of axonal forms of CMT. Our findings support the idea that MFN2 mutation status should be investigated in patients presenting with early-onset recessively inherited axonal CMT.

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“…Other compound heterozygous mutations, p.G108R and p.R707W, were reported in three siblings by Calvo et al (20) where the parents had no signs of peripheral neuropathy, had normal electrophysiological findings and each carried a single heterozygous mutation. Polke et al (27) reported three patients with recessive mutations. In two siblings the combination of missense mutations and deletion of 2 exons was observed.…”

Section: Discussionmentioning

confidence: 99%

Spectrum and frequencies of mutations in the MFN2 gene and its phenotypical expression in Czech hereditary motor and sensory neuropathy type II patients

Brožková

Posadka

Laššuthová

et al. 2013

Molecular Medicine Reports

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Abstract. The axonal type of Charcot-Marie-Tooth (CMT) disorders is genetically heterogeneous, therefore the causal mutation is unlikely to be observed, even in clinically well characterized patients. Mitofusin-2 (MFN2) gene mutations are the most frequent cause of axonal CMT disorders in a number of populations. There are two phenotypes; early onset, which is severe and late onset, which is a milder phenotype. A cohort of 139 unrelated Czech patients with axonal neuropathy was selected for sequencing and multiplex ligation-dependent probe amplification analysis (MLPA) testing of the MFN2 gene. A total of 11 MFN2 mutations were detected, with eight pathogenic mutations and three potentially rare benign polymorphisms. MLPA testing in 64 unrelated patients did not detect any exon duplication or deletion. The frequency of the pathogenic mutations detected in Czech hereditary motor and sensory neuropathy type II (HMSN II) patients was 7.2%. Early onset was more frequent among pathogenic mutation cases. Therefore we propose to examine the MFN2 gene mainly in patients with early and severe axonal CMT.

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Recessive axonal Charcot-Marie-Tooth disease due to compound heterozygous mitofusin 2 mutations

Cited by 71 publications

References 14 publications

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

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

Axonal Transport Defects in a Mitofusin 2 Loss of Function Model of Charcot-Marie-Tooth Disease in Zebrafish

Spectrum and frequencies of mutations in the MFN2 gene and its phenotypical expression in Czech hereditary motor and sensory neuropathy type II patients

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