Mutation screening of mitofusin 2 in Charcot-Marie-Tooth disease type 2

McCorquodale, Donald; Montenegro, Gladys; Peguero, Ainsley; Carlson, Nicole E.; Speziani, Fiorella; Price, Justin; Taylor, Stuart R.; Melanson, Michel; Vance, Jeffery M.; Züchner, Stephan

doi:10.1007/s00415-011-5910-7

Cited by 32 publications

(27 citation statements)

References 18 publications

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“…CMT2A, the most common axonal form of Charcot-Marie-Tooth disease, is caused by mitofusin-2 (MFN2) mutations [1–5]. CMT2A nerve biopsy specimens reveal axon loss, in some cases accompanied by abnormal mitochondrial groupings and morphologies in Schwann cells and axons [2,6,7].…”

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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“…This study underscores the fact that many variants may have been misannotated in the literature and that NGS is now bringing this issue to light 13 . For instance, a known pathogenic variant, p.Val705Ile, in mitofusin 2 ( MFN2 ) gene was found in two patients 29–31 . Mutations in this protein, which participates in mitochondrial fusion, cause two disorders of the peripheral nervous system: Charcot‐Marie‐Tooth disease type 2A2 (CMT2A2), and hereditary motor and sensory neuropathy VI.…”

Section: Resultsmentioning

confidence: 76%

Next‐generation sequencing for mitochondrial diseases: A wide diagnostic spectrum

Vasta

Merritt

Saneto

et al. 2012

Pediatrics International

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Sequencing only nuclear genes for RCC subunits and assembly factors may not provide the diagnostic answers for suspected patients with mitochondrial disorders. The present findings indicate that the diagnostic spectrum of mitochondrial disorders is much broader than previously thought, which could potentially lead to misdiagnosis and/or inappropriate treatment. Overall analytic sensitivity and precision appear acceptable for clinical testing. Despite the limitations in finding mutations in all patients, the present findings underscore the considerable clinical benefits of targeted next-generation sequencing and serve as a prototype for extending the clinical evaluation in this clinically heterogeneous patient group.

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“…The most frequent symptoms and signs were pes cavus (15 families), followed by scoliosis (12), tremor (9), optic atrophy (8), contracture (8), pain (5), hoarseness (2), hearing loss (2), transient sensory loss (2), vocal cord palsy (1), dysarthria (1), migraine (1), extensor plantar response (1), and stroke (1). Clinical severity also showed diverse ranges as indexed by FDS (0-8) and CMTNS .…”

Section: Identification Of Mfn2 Mutationsmentioning

confidence: 99%

“…ac.be/CMTMutations) (1,2). CMT2 is further divided into a large number of subtypes, among which mitofusin 2 (MFN2) gene (MIM# 608507) mutation is the most common cause (CMT2A, MIM#609260), accounting for 12-25% of CMT2 cases (7)(8)(9)(10)(11)(12), and ∼6% in general CMT cases (9,13). CMT is clinically and genetically heterogeneous; mutations in several different genes cause similar phenotypes and conversely, mutations in the same genes cause different phenotypes.…”

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confidence: 99%

A cohort study of MFN2 mutations and phenotypic spectrums in Charcot–Marie–Tooth disease 2A patients

et al. 2014

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Charcot-Marie-Tooth disease 2A (CMT2A) is the most common axonal form of peripheral neuropathy caused by a defect in the mitofusin 2 (MFN2) gene, which encodes an outer mitochondrial membrane GTPase. MFN2 mutations result in a large range of phenotypes. This study analyzed the prevalence of MFN2 mutation in Korean families with their assorted phenotypes (607 CMT families and 160 CMT2 families). Direct sequencing of the MFN2 coding exons or whole-exome sequencing has been applied to identify causative mutations. A total of 21 mutations were found in 36 CMT2 families. Comparative genotype-phenotype correlations impacting severity, onset age, and specific symptoms were assessed. Most mutations were seen in the GTPase domain (∼86%). A deletion mutation found in the transmembrane helices is reported for the first time, as well as five novel mutations at other domains. MFN2 mutations made up 5.9% of total CMT families, whereas 22.9% in CMT2 families, of which 27.8% occurred de novo. Interestingly, patient phenotypes ranged from mild to severe even for the same mutation, suggesting other factors influenced phenotype and penetrance. This CMT2A cohort study will be useful for molecular diagnosis and treatment of axonal neuropathy.

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Mutation screening of mitofusin 2 in Charcot-Marie-Tooth disease type 2

Cited by 32 publications

References 18 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

Next‐generation sequencing for mitochondrial diseases: A wide diagnostic spectrum

A cohort study of MFN2 mutations and phenotypic spectrums in Charcot–Marie–Tooth disease 2A patients

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