{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T12:14:18Z","timestamp":1791980058987,"version":"4.4.0"},"reference-count":66,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,3,22]],"date-time":"2025-03-22T00:00:00Z","timestamp":1742601600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,3,22]],"date-time":"2025-03-22T00:00:00Z","timestamp":1742601600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["ANR-16-CE14-0013"],"award-info":[{"award-number":["ANR-16-CE14-0013"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004923","name":"AFM-T\u00e9l\u00e9thon","doi-asserted-by":"publisher","award":["24219"],"award-info":[{"award-number":["24219"]}],"id":[{"id":"10.13039\/501100004923","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Idex University of Bordeaux","award":["GPR LIGHT"],"award-info":[{"award-number":["GPR LIGHT"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>Charcot\u2013Marie-Tooth Disease (CMT) is an inherited peripheral neuropathy with two main forms: demyelinating CMT1 and axonal CMT2. The most frequent subtype of CMT2 (CMT2A) is linked to mutations of <jats:italic>MFN2<\/jats:italic>, encoding a ubiquitously expressed GTP-binding protein anchored to the mitochondrial outer membrane and essential for mitochondrial fusion. The use of Next-Generation Sequencing has led to the identification of increasing numbers of <jats:italic>MFN2<\/jats:italic> variants, yet many of them remain of unknown significance, depriving patients of a clear diagnosis. In this work, we establish a cellular assay allowing to assess the impact of 12 known <jats:italic>MFN2<\/jats:italic> variants linked to CMT2A on mitochondrial fusion. The functional analysis revealed that out of the 12 selected <jats:italic>MFN2<\/jats:italic> mutations, only six exhibited reduced fusion activity. The classification of <jats:italic>MFN2<\/jats:italic> variants according to the results of the functional assay revealed a correlation between the fusion capacity, the age at onset of CMT2A and computational variant effect predictions relying on the analysis of the protein sequence. The functional assay and the results obtained will assist and improve the classification of novel <jats:italic>MFN2<\/jats:italic> variants identified in patients.<\/jats:p>","DOI":"10.1038\/s41598-025-93702-1","type":"journal-article","created":{"date-parts":[[2025,3,22]],"date-time":"2025-03-22T13:27:17Z","timestamp":1742650037000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["A cellular assay to determine the fusion capacity of MFN2 variants linked to Charcot\u2013Marie-Tooth disease of type 2\u00a0A"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4508-7934","authenticated-orcid":false,"given":"Chloe","family":"Barsa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"Perrin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudine","family":"David","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5413-611X","authenticated-orcid":false,"given":"Arnaud","family":"Mourier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9680-9263","authenticated-orcid":false,"given":"Manuel","family":"Rojo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,3,22]]},"reference":[{"key":"93702_CR1","doi-asserted-by":"publisher","first-page":"e021632","DOI":"10.1136\/bmjopen-2018-021632","volume":"8","author":"J Bacquet","year":"2018","unstructured":"Bacquet, J. et al. Molecular diagnosis of inherited peripheral neuropathies by targeted next-generation sequencing: molecular spectrum delineation. BMJ Open 8, e021632 (2018).","journal-title":"BMJ Open"},{"key":"93702_CR2","doi-asserted-by":"publisher","first-page":"644","DOI":"10.1038\/s41582-019-0254-5","volume":"15","author":"M Pipis","year":"2019","unstructured":"Pipis, M., Rossor, A. M., Laura, M. & Reilly, M. M. Next-generation sequencing in Charcot-Marie-Tooth disease: Opportunities and challenges. Nat. Rev. Neurol. 15, 644\u2013656 (2019).","journal-title":"Nat. Rev. Neurol."},{"key":"93702_CR3","doi-asserted-by":"publisher","first-page":"594","DOI":"10.1111\/cge.12432","volume":"87","author":"BO Choi","year":"2015","unstructured":"Choi, B. O. et al. A cohort study of MFN2 mutations and phenotypic spectrums in Charcot-Marie-Tooth disease 2A patients. Clin. Genet. 87, 594\u2013598 (2015).","journal-title":"Clin. Genet."},{"key":"93702_CR4","doi-asserted-by":"publisher","first-page":"3589","DOI":"10.1093\/brain\/awaa323","volume":"143","author":"M Pipis","year":"2020","unstructured":"Pipis, M. et al. Natural history of Charcot-Marie-Tooth disease type 2A: A large international multicentre study. Brain 143, 3589\u20133602 (2020).","journal-title":"Brain"},{"key":"93702_CR5","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1038\/ng1341","volume":"36","author":"S Z\u00fcchner","year":"2004","unstructured":"Z\u00fcchner, S. et al. Mutations in the mitochondrial GTPase Mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat. Genet. 36, 449\u2013451 (2004).","journal-title":"Nat. Genet."},{"key":"93702_CR6","doi-asserted-by":"publisher","first-page":"2093","DOI":"10.1093\/brain\/awl126","volume":"129","author":"K Verhoeven","year":"2006","unstructured":"Verhoeven, K. et al. MFN2 mutation distribution and genotype\/phenotype correlation in Charcot-Marie-Tooth type 2. Brain 129, 2093\u20132102 (2006).","journal-title":"Brain"},{"key":"93702_CR7","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.jns.2015.05.033","volume":"356","author":"G Stuppia","year":"2015","unstructured":"Stuppia, G. et al. MFN2-related neuropathies: Clinical features, molecular pathogenesis and therapeutic perspectives. J. Neurol. Sci. 356, 7\u201318 (2015).","journal-title":"J. Neurol. Sci."},{"key":"93702_CR8","doi-asserted-by":"publisher","first-page":"1678","DOI":"10.1212\/01.wnl.0000311275.89032.22","volume":"70","author":"GA Nicholson","year":"2008","unstructured":"Nicholson, G. A. et al. Severe early-onset axonal neuropathy with homozygous and compound heterozygous MFN2 mutations. Neurology 70, 1678\u20131681 (2008).","journal-title":"Neurology"},{"key":"93702_CR9","doi-asserted-by":"publisher","first-page":"1511","DOI":"10.1001\/archneurol.2009.284","volume":"66","author":"J Calvo","year":"2009","unstructured":"Calvo, J. et al. Genotype-phenotype correlations in Charcot-Marie-Tooth disease type 2 caused by mitofusin 2 mutations. Arch. Neurol. 66, 1511\u20131516 (2009).","journal-title":"Arch. Neurol."},{"key":"93702_CR10","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1111\/jns.12155","volume":"21","author":"PJ Tomaselli","year":"2016","unstructured":"Tomaselli, P. J. et al. Semi-dominant mutations in MFN2-related neuropathy and implications for genetic counselling. J. Peripher Nerv. Syst. 21, 52\u201354 (2016).","journal-title":"J. Peripher Nerv. Syst."},{"key":"93702_CR11","doi-asserted-by":"publisher","first-page":"867","DOI":"10.1242\/jcs.114.5.867","volume":"114","author":"A Santel","year":"2001","unstructured":"Santel, A. & Fuller, M. T. Control of mitochondrial morphology by a human mitofusin. J. Cell Sci. 114, 867\u2013874 (2001).","journal-title":"J. Cell Sci."},{"key":"93702_CR12","doi-asserted-by":"publisher","first-page":"1663","DOI":"10.1242\/jcs.115.8.1663","volume":"115","author":"M Rojo","year":"2002","unstructured":"Rojo, M., Legros, F., Chateau, D. & Lomb\u00e8s, A. Membrane topology and mitochondrial targeting of Mitofusins, ubiquitous mammalian homologs of the transmembrane GTPase Fzo. J. Cell Sci. 115, 1663\u20131674 (2002).","journal-title":"J. Cell Sci."},{"key":"93702_CR13","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1083\/jcb.200211046","volume":"160","author":"H Chen","year":"2003","unstructured":"Chen, H. et al. Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J. Cell. Biol. 160, 189\u2013200 (2003).","journal-title":"J. Cell. Biol."},{"key":"93702_CR14","doi-asserted-by":"crossref","unstructured":"Daste, F. et al. The heptad repeat domain 1 of Mitofusin has membrane destabilization function in mitochondrial fusion. EMBO Rep. 19, (2018).","DOI":"10.15252\/embr.201643637"},{"key":"93702_CR15","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1038\/s41594-018-0034-8","volume":"25","author":"L Yan","year":"2018","unstructured":"Yan, L. et al. Structural basis for GTP hydrolysis and conformational change of MFN1 in mediating membrane fusion. Nat. Struct. Mol. Biol. 25, 233\u2013243 (2018).","journal-title":"Nat. Struct. Mol. Biol."},{"key":"93702_CR16","doi-asserted-by":"publisher","first-page":"4914","DOI":"10.1038\/s41467-019-12912-0","volume":"10","author":"YJ Li","year":"2019","unstructured":"Li, Y. J. et al. Structural insights of human mitofusin-2 into mitochondrial fusion and CMT2A onset. Nat. Commun. 10, 4914 (2019).","journal-title":"Nat. Commun."},{"key":"93702_CR17","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1083\/jcb.200611080","volume":"176","author":"SA Detmer","year":"2007","unstructured":"Detmer, S. A. & Chan, D. C. Complementation between mouse Mfn1 and Mfn2 protects mitochondrial fusion defects caused by CMT2A disease mutations. J. Cell. Biol. 176, 405\u2013414 (2007).","journal-title":"J. Cell. Biol."},{"key":"93702_CR18","doi-asserted-by":"publisher","first-page":"R353","DOI":"10.1016\/j.cub.2017.03.024","volume":"27","author":"O Daumke","year":"2017","unstructured":"Daumke, O. & Roux, A. Mitochondrial homeostasis: how do dimers of Mitofusins mediate mitochondrial fusion? Curr. Biol. 27, R353\u2013R356 (2017).","journal-title":"Curr. Biol."},{"key":"93702_CR19","doi-asserted-by":"crossref","unstructured":"Cohen, M. M. & Tareste, D. Recent insights into the structure and function of Mitofusins in mitochondrial fusion. F1000Res 7, (2018).","DOI":"10.12688\/f1000research.16629.1"},{"key":"93702_CR20","doi-asserted-by":"publisher","first-page":"4145","DOI":"10.1523\/JNEUROSCI.6338-11.2012","volume":"32","author":"AL Misko","year":"2012","unstructured":"Misko, A. L., Sasaki, Y., Tuck, E., Milbrandt, J. & Baloh, R. H. Mitofusin2 mutations disrupt axonal mitochondrial positioning and promote axon degeneration. J. Neurosci. 32, 4145\u20134155 (2012).","journal-title":"J. Neurosci."},{"key":"93702_CR21","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1016\/j.cell.2010.02.026","volume":"141","author":"H Chen","year":"2010","unstructured":"Chen, H. et al. Mitochondrial fusion is required for MtDNA stability in skeletal muscle and tolerance of MtDNA mutations. Cell 141, 280\u2013289 (2010).","journal-title":"Cell"},{"key":"93702_CR22","doi-asserted-by":"publisher","first-page":"e1008085","DOI":"10.1371\/journal.pgen.1008085","volume":"15","author":"E Silva Ramos","year":"2019","unstructured":"Silva Ramos, E. et al. Mitochondrial fusion is required for regulation of mitochondrial DNA replication. PLoS Genet. 15, e1008085 (2019).","journal-title":"PLoS Genet."},{"key":"93702_CR23","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1083\/jcb.201411100","volume":"208","author":"A Mourier","year":"2015","unstructured":"Mourier, A. et al. Mitofusin 2 is required to maintain mitochondrial coenzyme Q levels. J. Cell Biol. 208, 429\u2013442 (2015).","journal-title":"J. Cell Biol."},{"key":"93702_CR24","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1038\/nature07534","volume":"456","author":"OM De Brito","year":"2008","unstructured":"De Brito, O. M. & Scorrano, L. Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456, 605\u2013610 (2008).","journal-title":"Nature"},{"key":"93702_CR25","doi-asserted-by":"publisher","first-page":"E2174","DOI":"10.1073\/pnas.1504880112","volume":"112","author":"R Filadi","year":"2015","unstructured":"Filadi, R. et al. Mitofusin 2 ablation increases Endoplasmic reticulum-mitochondria coupling. Proc. Natl. Acad. Sci. 112, E2174\u2013E2181 (2015).","journal-title":"Proc. Natl. Acad. Sci."},{"key":"93702_CR26","doi-asserted-by":"crossref","unstructured":"Richards, S. et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology.  17, 405\u2013424 (2015).","DOI":"10.1038\/gim.2015.30"},{"key":"93702_CR27","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1186\/s13073-019-0690-2","volume":"12","author":"SE Brnich","year":"2019","unstructured":"Brnich, S. E. et al. Recommendations for application of the functional evidence PS3\/BS3 criterion using the ACMG\/AMP sequence variant interpretation framework. Genome Med. 12, 3 (2019).","journal-title":"Genome Med."},{"key":"93702_CR28","doi-asserted-by":"publisher","first-page":"1012","DOI":"10.1002\/humu.24309","volume":"43","author":"S Gudmundsson","year":"2022","unstructured":"Gudmundsson, S. et al. Variant interpretation using population databases: lessons from GnomAD. Hum. Mutat. 43, 1012\u20131030 (2022).","journal-title":"Hum. Mutat."},{"key":"93702_CR29","doi-asserted-by":"publisher","first-page":"2163","DOI":"10.1016\/j.ajhg.2022.10.013","volume":"109","author":"V Pejaver","year":"2022","unstructured":"Pejaver, V. et al. Calibration of computational tools for missense variant pathogenicity classification and ClinGen recommendations for PP3\/BP4 criteria. Am. J. Hum. Genet. 109, 2163\u20132177 (2022).","journal-title":"Am. J. Hum. Genet."},{"key":"93702_CR30","doi-asserted-by":"publisher","first-page":"858286","DOI":"10.3389\/fcell.2022.858286","volume":"10","author":"M Zaman","year":"2022","unstructured":"Zaman, M. & Shutt, T. E. The role of impaired mitochondrial dynamics in MFN2-mediated pathology. Front. Cell. Dev. Biol. 10, 858286 (2022).","journal-title":"Front. Cell. Dev. Biol."},{"key":"93702_CR31","doi-asserted-by":"publisher","first-page":"5121","DOI":"10.1007\/s12035-020-02081-3","volume":"57","author":"R De Gioia","year":"2020","unstructured":"De Gioia, R. et al. Animal models of CMT2A: State-of-art and therapeutic implications. Mol. Neurobiol. 57, 5121\u20135129 (2020).","journal-title":"Mol. Neurobiol."},{"key":"93702_CR32","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1111\/jns5.12066","volume":"19","author":"AV Strickland","year":"2014","unstructured":"Strickland, A. V. et al. Characterization of the Mitofusin 2 R94W mutation in a knock-in mouse model. J. Peripher Nerv. Syst. 19, 152\u2013164 (2014).","journal-title":"J. Peripher Nerv. Syst."},{"key":"93702_CR33","doi-asserted-by":"crossref","unstructured":"Sato-Yamada, Y. et al. A SARM1-mitochondrial feedback loop drives neuropathogenesis in a Charcot-Marie-Tooth disease type 2A rat model. J. Clin. Invest. 132, (2022).","DOI":"10.1172\/JCI161566"},{"key":"93702_CR34","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1523\/JNEUROSCI.4798-06.2007","volume":"27","author":"RH Baloh","year":"2007","unstructured":"Baloh, R. H., Schmidt, R. E., Pestronk, A. & Milbrandt, J. Altered axonal mitochondrial transport in the pathogenesis of Charcot-Marie-Tooth disease from mitofusin 2 mutations. J. Neurosci. 27, 422\u2013430 (2007).","journal-title":"J. Neurosci."},{"key":"93702_CR35","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1038\/s41586-023-06045-0","volume":"625","author":"S Chen","year":"2024","unstructured":"Chen, S. et al. A genomic mutational constraint map using variation in 76,156 human genomes. Nature 625, 92\u2013100 (2024).","journal-title":"Nature"},{"key":"93702_CR36","doi-asserted-by":"publisher","first-page":"858","DOI":"10.1126\/science.1099793","volume":"305","author":"T Koshiba","year":"2004","unstructured":"Koshiba, T. et al. Structural basis of mitochondrial tethering by mitofusin complexes. Science 305, 858\u2013862 (2004).","journal-title":"Science"},{"key":"93702_CR37","doi-asserted-by":"crossref","unstructured":"El Fissi, N. et al. Mitofusin gain and loss of function drive pathogenesis in Drosophila models of CMT2A neuropathy. EMBO Rep. 19, (2018).","DOI":"10.15252\/embr.201745241"},{"key":"93702_CR38","doi-asserted-by":"publisher","first-page":"1036","DOI":"10.1001\/jamaneurol.2014.629","volume":"71","author":"F Bombelli","year":"2014","unstructured":"Bombelli, F. et al. Charcot-Marie-Tooth disease type 2A: from typical to rare phenotypic and genotypic features. JAMA Neurol. 71, 1036\u20131042 (2014).","journal-title":"JAMA Neurol."},{"key":"93702_CR39","doi-asserted-by":"publisher","first-page":"2125","DOI":"10.1093\/hmg\/ddu733","volume":"24","author":"C Dong","year":"2015","unstructured":"Dong, C. et al. Comparison and integration of deleteriousness prediction methods for nonsynonymous SNVs in whole exome sequencing studies. Hum. Mol. Genet. 24, 2125\u20132137 (2015).","journal-title":"Hum. Mol. Genet."},{"key":"93702_CR40","doi-asserted-by":"publisher","first-page":"1549","DOI":"10.1007\/s00439-022-02457-6","volume":"141","author":"P Katsonis","year":"2022","unstructured":"Katsonis, P., Wilhelm, K., Williams, A. & Lichtarge, O. Genome interpretation using in silico predictors of variant impact. Hum. Genet. 141, 1549\u20131577 (2022).","journal-title":"Hum. Genet."},{"key":"93702_CR41","doi-asserted-by":"publisher","unstructured":"van der Velde, K. J. et al. Gene-Aware variant interpretation for medical sequencing. Genome Biol. 1\u201310. https:\/\/doi.org\/10.1186\/s13059-016-1141-7 (2017).","DOI":"10.1186\/s13059-016-1141-7"},{"key":"93702_CR42","doi-asserted-by":"publisher","first-page":"372","DOI":"10.1038\/nature21077","volume":"542","author":"YL Cao","year":"2017","unstructured":"Cao, Y. L. et al. MFN1 structures reveal nucleotide-triggered dimerization critical for mitochondrial fusion. Nature 542, 372\u2013376 (2017).","journal-title":"Nature"},{"key":"93702_CR43","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1007\/978-981-13-8367-0_10","volume":"1158","author":"AJ Valente","year":"2019","unstructured":"Valente, A. J. et al. Quantification of mitochondrial network characteristics in health and disease. Adv. Exp. Med. Biol. 1158, 183\u2013196 (2019).","journal-title":"Adv. Exp. Med. Biol."},{"key":"93702_CR44","doi-asserted-by":"publisher","first-page":"e50703","DOI":"10.15252\/embr.202050703","volume":"21","author":"N El Fissi","year":"2020","unstructured":"El Fissi, N. et al. Mitofusin gain and loss of function drive pathogenesis in Drosophila models of CMT2A neuropathy. EMBO Rep. 21, e50703 (2020).","journal-title":"EMBO Rep."},{"key":"93702_CR45","doi-asserted-by":"publisher","first-page":"23615","DOI":"10.1074\/jbc.M112.379164","volume":"287","author":"T Zhao","year":"2012","unstructured":"Zhao, T. et al. Central role of mitofusin 2 in autophagosome-lysosome fusion in cardiomyocytes. J. Biol. Chem. 287, 23615\u201323625 (2012).","journal-title":"J. Biol. Chem."},{"key":"93702_CR46","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1126\/science.1231031","volume":"340","author":"Y Chen","year":"2013","unstructured":"Chen, Y. & Dorn, G. W. PINK1-phosphorylated mitofusin 2 is a parkin receptor for culling damaged mitochondria. Science 340, 471\u2013475 (2013).","journal-title":"Science"},{"key":"93702_CR47","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1002\/humu.23412","volume":"39","author":"C Saghira","year":"2018","unstructured":"Saghira, C. et al. Variant pathogenicity evaluation in the community-driven inherited neuropathy variant browser. Hum. Mutat. 39, 635\u2013642 (2018).","journal-title":"Hum. Mutat."},{"key":"93702_CR48","doi-asserted-by":"publisher","first-page":"D835","DOI":"10.1093\/nar\/gkz972","volume":"48","author":"MJ Landrum","year":"2020","unstructured":"Landrum, M. J. et al. ClinVar: Improvements to accessing data. Nucleic Acids Res. 48, D835\u2013D844 (2020).","journal-title":"Nucleic Acids Res."},{"key":"93702_CR49","doi-asserted-by":"publisher","first-page":"1796","DOI":"10.1038\/s41431-021-00959-x","volume":"29","author":"IFAC Fokkema","year":"2021","unstructured":"Fokkema, I. F. A. C. et al. The LOVD3 platform: Efficient genome-wide sharing of genetic variants. Eur. J. Hum. Genet. 29, 1796\u20131803 (2021).","journal-title":"Eur. J. Hum. Genet."},{"key":"93702_CR50","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s00439-013-1358-4","volume":"133","author":"PD Stenson","year":"2014","unstructured":"Stenson, P. D. et al. The human gene mutation database: Building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Hum. Genet. 133, 1\u20139 (2014).","journal-title":"Hum. Genet."},{"key":"93702_CR51","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1212\/01.wnl.0000171345.62270.29","volume":"65","author":"D Zhu","year":"2005","unstructured":"Zhu, D. et al. Charcot-Marie-Tooth with pyramidal signs is genetically heterogeneous: Families with and without MFN2 mutations. Neurology 65, 496\u2013497 (2005).","journal-title":"Neurology"},{"key":"93702_CR52","doi-asserted-by":"publisher","first-page":"2103","DOI":"10.1093\/brain\/awl174","volume":"129","author":"KW Chung","year":"2006","unstructured":"Chung, K. W. et al. Early onset severe and late-onset mild Charcot-Marie-Tooth disease with mitofusin 2 (MFN2) mutations. Brain 129, 2103\u20132118 (2006).","journal-title":"Brain"},{"key":"93702_CR53","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1186\/1471-2350-7-53","volume":"7","author":"K Engelfried","year":"2006","unstructured":"Engelfried, K. et al. Charcot-Marie-Tooth neuropathy type 2A: Novel mutations in the Mitofusin 2 gene (MFN2). BMC Med. Genet. 7, 53 (2006).","journal-title":"BMC Med. Genet."},{"key":"93702_CR54","doi-asserted-by":"publisher","first-page":"1690","DOI":"10.1212\/WNL.0b013e31821a441e","volume":"76","author":"SME Feely","year":"2011","unstructured":"Feely, S. M. E. et al. MFN2 mutations cause severe phenotypes in most patients with CMT2A. Neurology 76, 1690\u20131696 (2011).","journal-title":"Neurology"},{"key":"93702_CR55","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1016\/j.jns.2015.08.1528","volume":"358","author":"H Lv","year":"2015","unstructured":"Lv, H. et al. A cohort study of Han Chinese MFN2-related Charcot-Marie-Tooth 2A. J. Neurol. Sci. 358, 153\u2013157 (2015).","journal-title":"J. Neurol. Sci."},{"key":"93702_CR56","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1111\/jns.12159","volume":"21","author":"Y Xie","year":"2016","unstructured":"Xie, Y. et al. MFN2-related genetic and clinical features in a cohort of Chinese CMT2 patients. J. Peripher Nerv. Syst. 21, 38\u201344 (2016).","journal-title":"J. Peripher Nerv. Syst."},{"key":"93702_CR57","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1136\/jmg.2009.072488","volume":"47","author":"C Casasnovas","year":"2010","unstructured":"Casasnovas, C. et al. Phenotypic spectrum of MFN2 mutations in the Spanish population. J. Med. Genet. 47, 249\u2013256 (2010).","journal-title":"J. Med. Genet."},{"key":"93702_CR58","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1186\/s13073-020-00803-9","volume":"12","author":"X Liu","year":"2020","unstructured":"Liu, X., Li, C., Mou, C., Dong, Y. & Tu, Y. DbNSFP v4: a comprehensive database of transcript-specific functional predictions and annotations for human nonsynonymous and splice-site SNVs. Genome Med. 12, 103 (2020).","journal-title":"Genome Med."},{"key":"93702_CR59","doi-asserted-by":"publisher","first-page":"D891","DOI":"10.1093\/nar\/gkad1049","volume":"52","author":"PW Harrison","year":"2024","unstructured":"Harrison, P. W. et al. Ensembl 2024. Nucleic Acids Res. 52, D891\u2013D899 (2024).","journal-title":"Nucleic Acids Res."},{"key":"93702_CR60","doi-asserted-by":"publisher","first-page":"e12","DOI":"10.1093\/nar\/gku1189","volume":"43","author":"Y Xia","year":"2015","unstructured":"Xia, Y., Chu, W., Qi, Q. & Xun, L. New insights into the quikchange\u2122 process guide the use of phusion DNA polymerase for site-directed mutagenesis. Nucleic Acids Res. 43, e12 (2015).","journal-title":"Nucleic Acids Res."},{"key":"93702_CR61","doi-asserted-by":"publisher","first-page":"118942","DOI":"10.1016\/j.bbamcr.2020.118942","volume":"1868","author":"H Bahri","year":"2021","unstructured":"Bahri, H. et al. TMEM70 forms oligomeric scaffolds within mitochondrial cristae promoting in situ assembly of mammalian ATP synthase proton channel. Biochim. Biophys. Acta Mol. Cell. Res. 1868, 118942 (2021).","journal-title":"Biochim. Biophys. Acta Mol. Cell. Res."},{"key":"93702_CR62","doi-asserted-by":"publisher","first-page":"2297","DOI":"10.1016\/j.bbamcr.2012.08.007","volume":"1823","author":"M Frank","year":"2012","unstructured":"Frank, M. et al. Mitophagy is triggered by mild oxidative stress in a mitochondrial fission dependent manner. Biochim. Biophys. Acta  1823, 2297\u20132310 (2012).","journal-title":"Biochim. Biophys. Acta"},{"key":"93702_CR63","doi-asserted-by":"publisher","first-page":"1063","DOI":"10.1038\/sj.gt.3301206","volume":"7","author":"S Morita","year":"2000","unstructured":"Morita, S., Kojima, T. & Kitamura, T. Plat-E: An efficient and stable system for transient packaging of retroviruses. Gene Ther. 7, 1063\u20131066 (2000).","journal-title":"Gene Ther."},{"key":"93702_CR64","doi-asserted-by":"crossref","unstructured":"Fehse, B. B., Kustikova, O. S. O., Bubenheim, M. M. & Baum, C. C. Pois(s)on\u2013it\u2019s a question of dose. Gene Ther. 11, 879\u2013881 (2004).","DOI":"10.1038\/sj.gt.3302270"},{"key":"93702_CR65","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1007\/978-1-59745-365-3_1","volume":"372","author":"F Malka","year":"2007","unstructured":"Malka, F., Aur\u00e9, K., Goffart, S., Spelbrink, J. N. & Rojo, M. The mitochondria of cultured mammalian cells: I. Analysis by Immunofluorescence microscopy, histochemistry, subcellular fractionation, and cell fusion. Methods Mol. Biol. 372, 3\u201316 (2007).","journal-title":"Methods Mol. Biol."},{"key":"93702_CR66","doi-asserted-by":"publisher","unstructured":"Pe\u00f1alva, D.A., A.K. Monnappa, P. Natale, and I. L\u00f3pez-Montero. Mfn2-dependent fusion pathway of PE-enriched micron-sized vesicles. Proceedings of the National Academy of Sciences. 121, e2313609121. https:\/\/doi.org\/10.1073\/pnas.2313609121 (2024).","DOI":"10.1073\/pnas.2313609121"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-93702-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-93702-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-93702-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T02:49:10Z","timestamp":1742957350000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-93702-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,22]]},"references-count":66,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["93702"],"URL":"https:\/\/doi.org\/10.1038\/s41598-025-93702-1","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,22]]},"assertion":[{"value":"11 October 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 March 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 March 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"9971"}}