{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T16:49:37Z","timestamp":1780678177056,"version":"3.54.1"},"reference-count":29,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,3,12]],"date-time":"2022-03-12T00:00:00Z","timestamp":1647043200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004229","name":"Fondazione Pierfranco e Luisa Mariani","doi-asserted-by":"publisher","award":["CM23"],"award-info":[{"award-number":["CM23"]}],"id":[{"id":"10.13039\/501100004229","id-type":"DOI","asserted-by":"publisher"}]},{"name":"ERA PerMed","award":["project PerMiM, J49C2000019000-RE15"],"award-info":[{"award-number":["project PerMiM, J49C2000019000-RE15"]}]},{"name":"European Joint Programme on Rare Diseases","award":["project GENOMIT, J42F19000030006-RE17"],"award-info":[{"award-number":["project GENOMIT, J42F19000030006-RE17"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Endonuclease G (ENDOG) is a nuclear-encoded mitochondrial-localized nuclease. Although its precise biological function remains unclear, its proximity to mitochondrial DNA (mtDNA) makes it an excellent candidate to participate in mtDNA replication, metabolism and maintenance. Indeed, several roles for ENDOG have been hypothesized, including maturation of RNA primers during mtDNA replication, splicing of polycistronic transcripts and mtDNA repair. To date, ENDOG has been deemed as a determinant of cardiac hypertrophy, but no pathogenic variants or genetically defined patients linked to this gene have been described. Here, we report biallelic ENDOG variants identified by NGS in a patient with progressive external ophthalmoplegia, mitochondrial myopathy and multiple mtDNA deletions in muscle. The absence of the ENDOG protein in the patient\u2019s muscle and fibroblasts indicates that the identified variants are pathogenic. The presence of multiple mtDNA deletions supports the role of ENDOG in mtDNA maintenance; moreover, the patient\u2019s clinical presentation is very similar to mitochondrial diseases caused by mutations in other genes involved in mtDNA homeostasis. Although the patient\u2019s fibroblasts did not present multiple mtDNA deletions or delay in the replication process, interestingly, we detected an accumulation of low-level heteroplasmy mtDNA point mutations compared with age-matched controls. This may indicate a possible role of ENDOG in mtDNA replication or repair. Our report provides evidence of the association of ENDOG variants with mitochondrial myopathy.<\/jats:p>","DOI":"10.3390\/cells11060974","type":"journal-article","created":{"date-parts":[[2022,3,13]],"date-time":"2022-03-13T22:29:43Z","timestamp":1647210583000},"page":"974","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Biallelic Variants in ENDOG Associated with Mitochondrial Myopathy and Multiple mtDNA Deletions"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0640-9929","authenticated-orcid":false,"given":"Alessia","family":"Nasca","sequence":"first","affiliation":[{"name":"Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20126 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Legati","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20126 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3429-1809","authenticated-orcid":false,"given":"Megi","family":"Meneri","sequence":"additional","affiliation":[{"name":"Neurology Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"},{"name":"Department of Pathophysiology and Transplantation (DEPT), University of Milan, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6296-3417","authenticated-orcid":false,"given":"Melisa Emel","family":"Ermert","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20126 Milan, Italy"},{"name":"Department of Pathophysiology and Transplantation (DEPT), University of Milan, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Frascarelli","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20126 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1485-8983","authenticated-orcid":false,"given":"Nadia","family":"Zanetti","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20126 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Garbellini","sequence":"additional","affiliation":[{"name":"Neurology Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giacomo Pietro","family":"Comi","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology and Transplantation (DEPT), University of Milan, 20122 Milan, Italy"},{"name":"Neuromuscular and Rare Diseases Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Catania","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20126 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Costanza","family":"Lamperti","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20126 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dario","family":"Ronchi","sequence":"additional","affiliation":[{"name":"Neurology Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"},{"name":"Department of Pathophysiology and Transplantation (DEPT), University of Milan, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6564-3766","authenticated-orcid":false,"given":"Daniele","family":"Ghezzi","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20126 Milan, Italy"},{"name":"Department of Pathophysiology and Transplantation (DEPT), University of Milan, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/1423-0127-16-6","article-title":"Mutagenesis identifies the critical amino acid residues of human endonuclease G involved in catalysis, magnesium coordination, and substrate specificity","volume":"16","author":"Wu","year":"2009","journal-title":"J. Biomed. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1089\/dna.2014.2530","article-title":"Novel Cytoprotective Inhibitors for Apoptotic Endonuclease G","volume":"34","author":"Jang","year":"2015","journal-title":"DNA Cell Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1016\/j.exger.2010.03.002","article-title":"Role of Endonuclease G in Senescence-Associated Cell Death of Human Endothelial Cells\u2014ScienceDirect","volume":"45","author":"Diener","year":"2010","journal-title":"Exp. Gerontol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Sharma, P., and Sampath, H. (2019). Mitochondrial DNA Integrity: Role in Health and Disease. Cells, 8.","DOI":"10.3390\/cells8020100"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"18309","DOI":"10.18632\/oncotarget.24822","article-title":"Endonuclease G promotes mitochondrial genome cleavage and replication","volume":"9","author":"Wiehe","year":"2018","journal-title":"Oncotarget"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1038\/35083620","article-title":"Endonuclease G is an apoptotic DNase when released from mitochondria","volume":"412","author":"Li","year":"2001","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1038\/35083608","article-title":"Mitochondrial endonuclease G is important for apoptosis in C. elegans","volume":"412","author":"Parrish","year":"2001","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1007\/BF00309540","article-title":"Analysis of the role of the NUC1 endo\/exonuclease in yeast mitochondrial DNA recombination","volume":"25","author":"Zassenhaus","year":"1994","journal-title":"Curr. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1128\/MCB.25.1.294-302.2005","article-title":"Generation and Characterization of Endonuclease G Null Mice","volume":"25","author":"Irvine","year":"2005","journal-title":"Mol. Cell Biol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Yan, C., Duanmu, X., Zeng, L., Liu, B., and Song, Z. (2019). Mitochondrial DNA: Distribution, Mutations, and Elimination. Cells, 8.","DOI":"10.3390\/cells8040379"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1038\/nature10490","article-title":"Endonuclease G is a novel determinant of cardiac hypertrophy and mitochondrial function","volume":"478","author":"Ye","year":"2011","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1326","DOI":"10.1016\/j.bbabio.2016.02.022","article-title":"New genes and pathomechanisms in mitochondrial disorders unraveled by NGS technologies","volume":"1857","author":"Legati","year":"2016","journal-title":"Biochim. Biophys. Acta Bioenerg."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1016\/j.jmoldx.2021.03.002","article-title":"Current and new Next-Generation Sequencing approaches to study mitochondrial DNA","volume":"23","author":"Legati","year":"2021","journal-title":"J. Mol. Diagn."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.ajhg.2012.12.014","article-title":"Mutations in DNA2 link progressive myopathy to mitochondrial DNA instability","volume":"92","author":"Ronchi","year":"2013","journal-title":"Am. J. Hum. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.ajhg.2015.05.013","article-title":"RNASEH1 Mutations Impair mtDNA Replication and Cause Adult-Onset Mitochondrial Encephalomyopathy","volume":"97","author":"Reyes","year":"2015","journal-title":"Am. J. Hum. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.bbabio.2004.09.006","article-title":"Clinical and molecular findings in children with complex I deficiency","volume":"1659","author":"Bugiani","year":"2004","journal-title":"Biochim. Biophys. Acta Bioenerg."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"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","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.1002\/humu.24081","article-title":"Homozygous mutations in C1QBP as cause of progressive external ophthalmoplegia (PEO) and mitochondrial myopathy with multiple mtDNA deletions","volume":"41","author":"Marchet","year":"2020","journal-title":"Hum. Mutat."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Kennedy, S.R., Salk, J.J., Schmitt, M.W., and Loeb, L.A. (2013). Ultra-sensitive sequencing reveals an age-related increase in somatic mitochondrial mutations that are inconsistent with oxidative damage. PLoS Genet., 9.","DOI":"10.1371\/journal.pgen.1003794"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Itsara, L.S., Kennedy, S.R., Fox, E.J., Yu, S., Hewitt, J.J., Sanchez-Contreras, M., Cardozo-Pelaez, F., and Pallanck, L.J. (2014). Oxidative Stress Is Not a Major Contributor to Somatic Mitochondrial DNA Mutations. PLoS Genet., 10.","DOI":"10.1371\/journal.pgen.1003974"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3347","DOI":"10.1167\/iovs.09-4660","article-title":"Somatic Mitochondrial DNA Deletions Accumulate to High Levels in Aging Human Extraocular Muscles","volume":"51","author":"Borthwick","year":"2010","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1016\/j.bbadis.2017.02.017","article-title":"Mitochondrial DNA maintenance defects","volume":"1863","author":"Craigen","year":"2017","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4612","DOI":"10.1093\/hmg\/ddu176","article-title":"Dissecting the mechanisms underlying the accumulation of mitochondrial DNA deletions in human skeletal muscle","volume":"23","author":"Campbell","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1212\/WNL.40.1.24","article-title":"Widespread tissue distribution of mitochondrial DNA deletions in Kearns-Sayre syndrome","volume":"40","author":"Shanske","year":"1990","journal-title":"Neurology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1083\/jcb.201010024","article-title":"Mitochondrial DNA mutations in disease and aging","volume":"193","author":"Park","year":"2011","journal-title":"J. Cell Biol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Kujoth, G.C., Bradshaw, P.C., Haroon, S., and Prolla, T.A. (2007). The role of mitochondrial DNA mutations in mammalian aging. PLoS Genet., 3.","DOI":"10.1371\/journal.pgen.0030024"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.jns.2007.07.006","article-title":"Age-related mitochondrial DNA point mutations in patients with mitochondrial myopathy","volume":"263","author":"Kiyomoto","year":"2007","journal-title":"J. Neurol. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"669379","DOI":"10.3389\/fcell.2021.669379","article-title":"The Mitochondrial Response to DNA Damage","volume":"9","author":"Rong","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"11244","DOI":"10.1093\/nar\/gkaa804","article-title":"Mechanisms of replication and repair in mitochondrial DNA deletion formation","volume":"48","author":"Fontana","year":"2020","journal-title":"Nucleic Acids Res."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/6\/974\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:35:27Z","timestamp":1760135727000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/6\/974"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,12]]},"references-count":29,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2022,3]]}},"alternative-id":["cells11060974"],"URL":"https:\/\/doi.org\/10.3390\/cells11060974","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,12]]}}}