MFN2 mutation distribution and genotype/phenotype correlation in Charcot-Marie-Tooth type 2

Verhoeven, Kristien; Claeys, Kristl G.; Züchner, Stephan; Schröder, Johann Michael; Weis, Joachim; Ceuterick, C.; Jordanova, Albena; Nelis, Eva; Vriendt, Els De; Hul, Matthias Van; Seeman, Pavel; Mazanec, Radim; Saifi, Gulam Mustafa; Szigeti, Kinga; Mancías, Pedro; Butler, Ian J.; Kochański, Andrzej; Ryniewicz, Barbara; Bleecker, Jan De; Bergh, Peter Van den; Verellen, Christine; Coster, Rudy Van; Goemans, Nathalie; Auer‐Grumbach, Michaela; Robberecht, Wim; Rašić, V. Milić; Nevo, Yoram; Tournev, I.; Guergueltcheva, Velina; Roelens, Filip; Vieregge, P.; Vinci, Paolo; Moreno, M. T.; Christen, H.-J.; Shy, Michael E.; Lupski, James R.; Vance, Jeffery M.; Jonghe, Peter De; Timmerman, Vincent

doi:10.1093/brain/awl126

Cited by 348 publications

(396 citation statements)

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“…However, its frequency was lower than 20-30% reported in other countries. 14,31,32 Following the MFN2 mutations, we found GJB1 or MPZ mutations in 4-5% of patients with axonal CMT (Table 2). GARS or GDAP1 mutations are very rare and were detected in one patient each.…”

Section: Discussionmentioning

confidence: 91%

Molecular diagnosis and clinical onset of Charcot–Marie–Tooth disease in Japan

et al. 2011

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To study the genetic background of Japanese Charcot-Marie-Tooth disease (CMT) patients, we analyzed qualitative and quantitative changes in the disease-causing genes mainly by denaturing high performance liquid chromatography and multiplex ligation-dependent probe analysis in 227 patients with demyelinating CMT and 127 patients with axonal CMT. In demyelinating CMT, we identified 53 patients with PMP22 duplication, 10 patients with PMP22 mutations, 20 patients with MPZ mutations, eight patients with NEFL mutations, 19 patients with GJB1 mutations, one patient with EGR2 mutation, five patients with PRX mutations and no mutations in 111 patients. In axonal CMT, we found 14 patients with MFN2 mutations, one patient with GARS mutation, five patients with MPZ mutations, one patient with GDAP1 mutation, six patients with GJB1 mutations and no mutations in 100 patients. Most of the patients carrying PMP22, MPZ, NEFL, PRX and MFN2 mutations showed early onset, whereas half of the patients carrying PMP22 duplication and all patients with GJB1 or MPZ mutations showing axonal phenotype were adult onset. Our data showed that a low prevalence of PMP22 duplication and high frequency of an unknown cause are features of Japanese CMT. Low prevalence of PMP22 duplication is likely associated with the mild symptoms due to genetic and/or epigenetic modifying factors.

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Section: Discussionmentioning

confidence: 91%

Molecular diagnosis and clinical onset of Charcot–Marie–Tooth disease in Japan

et al. 2011

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“…39,40 Future studies to identify how particular MFN2 mutations mechanistically relate to differing clinical symptoms will be invaluable for understanding how alterations in this complex protein cause axonal neuropathy. 41 Another molecule associated with dominant and recessive inheritance of CMT is ganglioside-induced differentiationassociated protein-1 (GDAP1; OMIM no. 606598, http:// www.ncbi.nlm.nih.gov/omim).…”

Section: Mitochondrial Dynamicsmentioning

confidence: 99%

Axon Transport and Neuropathy

Tourtellotte

2016

The American Journal of Pathology

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Peripheral neuropathies are highly prevalent and are most often associated with chronic disease, side effects from chemotherapy, or toxic-metabolic abnormalities. Neuropathies are less commonly caused by genetic mutations, but studies of the normal function of mutated proteins have identified particular vulnerabilities that often implicate mitochondrial dynamics and axon transport mechanisms. Hereditary sensory and autonomic neuropathies are a group of phenotypically related diseases caused by monogenic mutations that primarily affect sympathetic and sensory neurons. Here, I review evidence to indicate that many genetic neuropathies are caused by abnormalities in axon transport. Moreover, in hereditary sensory and autonomic neuropathies. There may be specific convergence on gene mutations that disrupt nerve growth factor signaling, upon which sympathetic and sensory neurons critically depend. (Am J Pathol 2016, 186: 489e499; http://dx

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“…Strikingly, most recent studies reveal that abnormal mitochondrial fusion and fission participate in the regulation of apoptosis 5,6 . In particular, they are related to a variety of diseases such as skeletal muscle disorders [7][8][9] , peripheral neuropathy CharcotMarie-Tooth type 2A 10,11 and neurodegeneration 12 .…”

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confidence: 99%

miR-484 regulates mitochondrial network through targeting Fis1

et al. 2012

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mitochondria constantly undergo fusion and fission, two necessary processes for the maintenance of organelle fidelity. The abnormal mitochondrial fission participates in the pathogenesis of many diseases, but its regulation remains poorly understood. Here we show that miR-484 can suppress translation of mitochondrial fission protein Fis1, and inhibit Fis1-mediated fission and apoptosis in cardiomyocytes and in the adrenocortical cancer cells. We demonstrate that Fis1 is necessary for mitochondrial fission and apoptosis, and is upregulated during anoxia, whereas miR-484 is downregulated. miR-484 is able to attenuate Fis1 upregulation and mitochondrial fission, by binding to the amino acid coding sequence of Fis1 and inhibiting its translation. In exploring the underlying mechanism of miR-484 downregulation upon apoptosis, we observe that Foxo3a transactivates miR-484 expression. Foxo3a transgenic or knockout mice exhibit, respectively, a high or low level of miR-484 and a reduced or enhanced mitochondrial fission, apoptosis and myocardial infarction. our data reveal a model of mitochondrial fission regulation by a microRnA.

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MFN2 mutation distribution and genotype/phenotype correlation in Charcot-Marie-Tooth type 2

Cited by 348 publications

References 21 publications

Molecular diagnosis and clinical onset of Charcot–Marie–Tooth disease in Japan

Molecular diagnosis and clinical onset of Charcot–Marie–Tooth disease in Japan

Axon Transport and Neuropathy

miR-484 regulates mitochondrial network through targeting Fis1

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