MFN2point mutations occur in 3.4% of Charcot-Marie-Tooth families. An investigation of 232 Norwegian CMT families

Braathen, Geir J.; Sand, Jette C; Lobato, Ana Christina de Lacerda; Høyer, Helle; Russell, Michael Bjørn

doi:10.1186/1471-2350-11-48

Cited by 46 publications

(39 citation statements)

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“…(Arg468His)C5[29–31]8CMT1 MFN2 NM_014874.3c.1403G > Ap. (Arg468His)C5[29–31]9CMT1 MFN2 NM_014874.3c.2119A > Gp. (Arg707Trp)C5[31]10CMT2 PMP22 NM_000304.2c.448G > Cp.…”

Section: Resultsmentioning

confidence: 99%

Application of targeted multi-gene panel testing for the diagnosis of inherited peripheral neuropathy provides a high diagnostic yield with unexpected phenotype-genotype variability

et al. 2015

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BackgroundInherited peripheral neuropathy (IPN) is a clinically and genetically heterogeneous group of disorders with more than 90 genes associated with the different subtypes. Sequential gene screening is gradually being replaced by next generation sequencing (NGS) applications.MethodsWe designed and validated a targeted NGS panel assay including 56 genes associated with known causes of IPN. We report our findings following NGS panel testing of 448 patients with different types of clinically-suspected IPN.ResultsGenetic diagnosis was achieved in 137 patients (31 %) and involved 195 pathogenic variants in 31 genes. 93 patients had pathogenic variants in genes where a resulting phenotype follows dominant inheritance, 32 in genes where this would follow recessive inheritance, and 12 presented with X-linked disease.Almost half of the diagnosed patients (64) had a pathogenic variant either in genes not previously available for routine diagnostic testing in a UK laboratory (50 patients) or in genes whose primary clinical association was not IPN (14).Seven patients had a pathogenic variant in a gene not hitherto indicated from their phenotype and three patients had more than one pathogenic variant, explaining their complex phenotype and providing information essential for accurate prediction of recurrence risks.ConclusionsOur results demonstrate that targeted gene panel testing is an unbiased approach which overcomes the limitations imposed by limited existing knowledge for rare genes, reveals high heterogeneity, and provides high diagnostic yield. It is therefore a highly efficient and cost effective tool for achieving a genetic diagnosis for IPN.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-015-0224-8) contains supplementary material, which is available to authorized users.

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“…(Arg468His)C5[29–31]8CMT1 MFN2 NM_014874.3c.1403G > Ap. (Arg468His)C5[29–31]9CMT1 MFN2 NM_014874.3c.2119A > Gp. (Arg707Trp)C5[31]10CMT2 PMP22 NM_000304.2c.448G > Cp.…”

Section: Resultsmentioning

confidence: 99%

Application of targeted multi-gene panel testing for the diagnosis of inherited peripheral neuropathy provides a high diagnostic yield with unexpected phenotype-genotype variability

et al. 2015

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“…Thus, studies of the exact functional mechanism of Mfn2, which has been confirmed to exert a potential apoptotic effect via the mitochondrial apoptotic pathway (5), are essential. In the present study, we investigated Mfn2, which has been widely studied in Charcot-Marie-Tooth disease (16). Mfn2 is known to be correlated with antitumor activity in a number of malignancies (5-7); however, its effect in breast cancers has not been previously reported.…”

Section: Mfn2 Suppresses Cell Cycle Progression Via the Pi3k/akt Signmentioning

confidence: 99%

Pro-apoptotic and anti-proliferative effects of mitofusin-2 via PI3K/Akt signaling in breast cancer cells

Chang

et al. 2015

Oncology Letters

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Abstract. The mitochondrial GTPase mitofusin-2 (Mfn2) gene is a novel gene characterized as a cell proliferation inhibitor. Mfn2 has previously been reported to play a role in regulating cell proliferation, apoptosis and differentiation in a number of cell types. However, there are no studies on the effect of Mfn2 in breast cancer. In this study, we aimed to elucidate the function and mechanism of Mfn2 in breast cancer. A plasmid encoding the complete Mfn2 open reading frame (pEGFP-Mfn2) was used to infect breast cancer cells. The effect of Mfn2 on proliferation was assessed by methyl thiazolyl tetrazolium and bromodeoxyuridine incorporation analyses. Flow cytometry, immunofluorescence and western blot analyses were used to test the effects of Mfn2 on cell cycle distribution and apoptosis. Additionally, the PI3K/Akt signaling pathway was analyzed after pEGFP-Mfn2 was transfected into MCF-7 cells. The results revealed that Mfn2 suppressed the proliferation of MCF-7 cells by regulating more cells at the G0/G1 phase and decreasing proliferating cell nuclear antigen and cyclin A expression. The results also demonstrated that the PI3K/Akt signaling pathway is involved in Mfn2-regulated proliferation and apoptosis. Taken together, this indicates that Mfn2 mediates MCF-7 cell proliferation and apoptosis via the PI3K/Akt signaling pathway. Mfn2 may thus be a significant therapeutic target in the treatment of breast cancer. IntroductionThe mitochondrial GTPase mitofusin-2 (Mfn2) gene, which is also called the hyperplasia suppressor gene, was originally identified in vascular smooth muscle cells from spontaneously hypertensive rats, which exhibited markedly lower expression than Wistar-Kyoto rats (1). Mfn2 localizes to the mitochondrial outer membrane and plays an essential role in mitochondrial fusion, thus regulating mitochondrial morphology and function. Further research has indicated that Mfn2 has a potential apoptotic effect mediated by the mitochondrial apoptotic pathway (1-3). Chen et al (4) demonstrated that Mfn2 notably suppresses cell growth and proliferation in a number of tumor cell lines through the inhibition of the Ras-ERK MAPK signaling pathway. Recently, Mfn2 has become a focal point in tumor research. Several studies have investigated the function of Mfn2 in various malignancies, including hepatocellular, urinary bladder and gastric cancers, and Mfn2 is considered to perform pro-apoptotic and anti-proliferative functions (5-7).Clinical and epidemiological evidence reveals that estrogens participate in the initiation and development of human breast cancer (8,9). Understanding the role of estrogen receptor (ER) α and β in the pathogenesis of breast cancer is essential, since the effects of estrogen are mediated through these two ERs (10). Although the function of ERα has been established and this receptor remains the most significant marker of the response to hormonal therapy in breast cancer, the role of ERβ remains elusive as a result of a number of conflicting studies (11). Our previous study demonstrat...

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“…Norwegian CMT cases and confirmed that MFN2 gene mutation can also cause intermediate CMT [80] . Of these genes, some are also associated with the classical CMT1 [81] .…”

Section: Plekhg5 and The Ri-cmtc Phenotypementioning

confidence: 62%

Intermediate Charcot-Marie-Tooth disease

Liu

Zhang

2014

Neurosci. Bull.

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Charcot-Marie-Tooth (CMT) disease is a common neurogenetic disorder and its heterogeneity is a challenge for genetic diagnostics. The genetic diagnostic procedures for a CMT patient can be explored according to the electrophysiological criteria: very slow motor nerve conduction velocity (MNCV) (<15 m/s), slow MNCV (15-25 m/s), intermediate MNCV (25-45 m/s), and normal MNCV (>45 m/s). Based on the inheritance pattern, intermediate CMT can be divided into dominant (DI-CMT) and recessive types (RI-CMT). GJB1 is currently considered to be associated with X-linked DI-CMT, and MPZ, INF2, DNM2, YARS, GNB4, NEFL, and MFN2 are associated with autosomal DI-CMT. Moreover, GDAP1, KARS, and PLEKHG5 are associated with RI-CMT. Identifi cation of these genes is not only important for patients and families but also provides new information about pathogenesis. It is hoped that this review will lead to a better understanding of intermediate CMT and provide a detailed diagnostic procedure for intermediate CMT.

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MFN2point mutations occur in 3.4% of Charcot-Marie-Tooth families. An investigation of 232 Norwegian CMT families

Cited by 46 publications

References 22 publications

Application of targeted multi-gene panel testing for the diagnosis of inherited peripheral neuropathy provides a high diagnostic yield with unexpected phenotype-genotype variability

Application of targeted multi-gene panel testing for the diagnosis of inherited peripheral neuropathy provides a high diagnostic yield with unexpected phenotype-genotype variability

Pro-apoptotic and anti-proliferative effects of mitofusin-2 via PI3K/Akt signaling in breast cancer cells

Intermediate Charcot-Marie-Tooth disease

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