{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T05:50:51Z","timestamp":1773813051516,"version":"3.50.1"},"reference-count":55,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2019,12,4]],"date-time":"2019-12-04T00:00:00Z","timestamp":1575417600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Our data first represent the variety of Leber\u2019s hereditary optic neuropathy (LHON) mutations in Western Siberia. LHON is a disorder caused by pathogenic mutations in the mitochondrial DNA (mtDNA), inherited maternally and presents mainly in young adults, predominantly males. Clinically, LHON manifests itself as painless central vision loss, resulting in early onset of disability. The epidemiology of LHON has not been fully investigated yet. In this study, we report 44 genetically unrelated families with LHON manifestation. We performed whole mtDNA genome sequencing and provided genealogical and molecular genetic data on mutations and haplogroup background of LHON patients. Known \u201cprimary\u201d pathogenic mtDNA mutations (MITOMAP) were found in 32 families: m.11778G&gt;A represents 53.10% (17\/32), m.3460G&gt;A\u201421.90% (7\/32), m.14484T&gt;C\u201318.75% (6\/32), and rare m.10663T&gt;C and m.3635G&gt;A represent 6.25% (2\/32). We describe potentially pathogenic m.4659G&gt;A in one subject without known pathogenic mutations, and potentially pathogenic m.6261G&gt;A, m.8412T&gt;C, m.8551T&gt;C, m.9444C&gt;T, m.9921G&gt;A, and m.15077G&gt;A in families with known pathogenic mutations confirmed. We suppose these mutations could contribute to the pathogenesis of optic neuropathy development. Our results indicate that haplogroup affiliation and mutational spectrum of the Western Siberian LHON cohort substantially deviate from those of European populations.<\/jats:p>","DOI":"10.3390\/cells8121574","type":"journal-article","created":{"date-parts":[[2019,12,5]],"date-time":"2019-12-05T03:16:36Z","timestamp":1575515796000},"page":"1574","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Mitochondrial DNA Variation of Leber\u2019s Hereditary Optic Neuropathy in Western Siberia"],"prefix":"10.3390","volume":"8","author":[{"given":"Elena","family":"Starikovskaya","sequence":"first","affiliation":[{"name":"Laboratory of Human Molecular Genetics, Institute of Molecular and Cellular Biology, SBRAS, Novosibirsk 630090, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sofia","family":"Shalaurova","sequence":"additional","affiliation":[{"name":"Laboratory of Human Molecular Genetics, Institute of Molecular and Cellular Biology, SBRAS, Novosibirsk 630090, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stanislav","family":"Dryomov","sequence":"additional","affiliation":[{"name":"Laboratory of Human Molecular Genetics, Institute of Molecular and Cellular Biology, SBRAS, Novosibirsk 630090, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8833-7593","authenticated-orcid":false,"given":"Azhar","family":"Nazhmidenova","sequence":"additional","affiliation":[{"name":"Laboratory of Human Molecular Genetics, Institute of Molecular and Cellular Biology, SBRAS, Novosibirsk 630090, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalia","family":"Volodko","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Alberta, Edmonton, AB T6G 2R3, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Igor","family":"Bychkov","sequence":"additional","affiliation":[{"name":"Novosibirsk Branch of S.N. Fedorov NMRC \u201cMNTK Eye Microsurgery\u201d, Moscow 127486, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5448-9679","authenticated-orcid":false,"given":"Ilia","family":"Mazunin","sequence":"additional","affiliation":[{"name":"Center of Life Sciences, Skolkovo Institute of Science and Technology, Skolkovo 121205, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rem","family":"Sukernik","sequence":"additional","affiliation":[{"name":"Laboratory of Human Molecular Genetics, Institute of Molecular and Cellular Biology, SBRAS, Novosibirsk 630090, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,12,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1001\/archneur.62.5.730","article-title":"Severe impairment of complex I-driven adenosine triphosphate synthesis in leber hereditary optic neuropathy cybrids","volume":"62","author":"Baracca","year":"2005","journal-title":"Arch. Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"20065","DOI":"10.1073\/pnas.1217113109","article-title":"Mouse mtDNA mutant model of Leber hereditary optic neuropathy","volume":"109","author":"Lin","year":"2012","journal-title":"Proc Natl. Acad. Sci. USA"},{"key":"ref_3","first-page":"242","article-title":"Leber Hereditary Optic Neuropathy-Light at the End of the Tunnel?","volume":"7","author":"Kim","year":"2018","journal-title":"Asia Pac. J. Opthalmol. (Phila)"},{"key":"ref_4","first-page":"1165","article-title":"Leber hereditary optic neuropathy: Current perspectives","volume":"9","author":"Meyerson","year":"2015","journal-title":"Clin. Ophthalmol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1136\/bjophthalmol-2016-310072","article-title":"Childhood-onset Leber hereditary optic neuropathy","volume":"101","author":"Majander","year":"2017","journal-title":"Br. J. Ophthalmol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2187","DOI":"10.2147\/OPTH.S120197","article-title":"Leber\u2019s hereditary optic neuropathy is multiorgan not mono-organ","volume":"10","author":"Finsterer","year":"2016","journal-title":"Clin. Ophthalmol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Haas, R.H. (2019). Mitochondrial Dysfunction in Aging and Diseases of Aging. Biology, 8.","DOI":"10.3390\/biology8020048"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Barcelos, I.P.d., Troxell, R.M., and Graves, J.S. (2019). Mitochondrial dysfunction and multiple sclerosis. Biology, 8.","DOI":"10.3390\/biology8020037"},{"key":"ref_9","first-page":"481","article-title":"Primary pathogenic mtDNA mutations in multigeneration pedigrees with Leber hereditary optic neuropathy","volume":"59","author":"Mackey","year":"1996","journal-title":"Am. J. Hum. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1080\/02713689808951221","article-title":"Spectrum of pathogenic mitochondrial DNA mutations and clinical features in Japanese families with Leber\u2019s hereditary optic neuropathy","volume":"17","author":"Mashima","year":"1998","journal-title":"Curr. Eye Res."},{"key":"ref_11","first-page":"2687","article-title":"Clinical characterization and mitochondrial DNA sequence variations in Leber hereditary optic neuropathy","volume":"18","author":"Kumar","year":"2012","journal-title":"Mol. Vis."},{"key":"ref_12","first-page":"334","article-title":"Pan-American mDNA haplogroups in Chilean patients with Leber\u2019s hereditary optic neuropathy","volume":"20","author":"Romero","year":"2014","journal-title":"Mol. Vis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4778","DOI":"10.1167\/iovs.14-16158","article-title":"Prevalence of Mitochondrial ND4 Mutations in 1281 Han Chinese Subjects With Leber\u2019s Hereditary Optic Neuropathy","volume":"56","author":"Jiang","year":"2015","journal-title":"Invest Ophthalmol. Vis. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3923","DOI":"10.1167\/iovs.16-20695","article-title":"Leber\u2019s hereditary optic neuropathy\u2013specific mutation m.11778G>A exists on diverse mitochondrial haplogroups in India","volume":"58","author":"Khan","year":"2017","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1086\/432491","article-title":"A \u201cFille du Roy\u201d introduced the T14484C Leber hereditary optic neuropathy mutation in French Canadians","volume":"77","author":"Laberge","year":"2005","journal-title":"Am. J. Hum. Genet."},{"key":"ref_16","first-page":"1208","article-title":"Segregation patterns and heteroplasmy prevalence in Leber\u2019s hereditary optic neuropathy","volume":"42","author":"Jacobi","year":"2001","journal-title":"Inves.t Ophthalmol. Vis. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2317","DOI":"10.1093\/brain\/awp158","article-title":"Gene-environment interactions in Leber hereditary optic neuropathy","volume":"132","author":"Kirkman","year":"2009","journal-title":"Brain"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.exer.2013.08.007","article-title":"Identification of the variants in PARL, the nuclear modifier gene, responsible for the expression of LHON patients in Thailand","volume":"116","author":"Istikharah","year":"2013","journal-title":"Exp. Eye Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1038\/sj.ejhg.5201828","article-title":"Epidemiology and penetrance of Leber hereditary optic neuropathy in Finland","volume":"15","author":"Puomila","year":"2007","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"461","DOI":"10.5301\/ejo.5000055","article-title":"Meta-analysis of the prevalence of Leber hereditary optic neuropathy mtDNA mutations in Europe","volume":"22","author":"Mascialino","year":"2012","journal-title":"Eur. J. Ophthalmol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1007\/s004390100538","article-title":"Novel mtDNA mutations and oxidative phosphorylation dysfunction in Russian LHON families","volume":"109","author":"Brown","year":"2001","journal-title":"Hum. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1007\/s00439-001-0660-8","article-title":"The role of mtDNA background in disease expression: A new primary LHON mutation associated with Western Eurasian haplogroup","volume":"110","author":"Brown","year":"2002","journal-title":"J. Hum. Genet."},{"key":"ref_23","first-page":"89","article-title":"Spectrum of pathogenic mtDNA mutations in Leber hereditary optic neuropathy families from Siberia","volume":"42","author":"Starikovskaia","year":"2006","journal-title":"Genetika"},{"key":"ref_24","first-page":"598","article-title":"Acute and late-onset optic atrophy due to a novel OPA1 mutation leading to a mitochondrial coupling defect","volume":"15","author":"Nochez","year":"2009","journal-title":"Mol. Vis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1016\/j.ajhg.2012.03.002","article-title":"A \u201cCopernican\u201d reassessment of the human mitochondrial DNA tree from its root","volume":"90","author":"Behar","year":"2012","journal-title":"Am. J. Hum. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"E386","DOI":"10.1002\/humu.20921","article-title":"Updated comprehensive phylogenetic tree of global human mitochondrial DNA variation","volume":"30","author":"Kayser","year":"2009","journal-title":"Hum. Mutat."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"D611","DOI":"10.1093\/nar\/gki079","article-title":"MITOMAP: A human mitochondrial genome database--2004 update","volume":"33","author":"Brandon","year":"2005","journal-title":"Nucleic Acids Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"D749","DOI":"10.1093\/nar\/gkj010","article-title":"mtDB: Human Mitochondrial Genome Database, a resource for population genetics and medical sciences","volume":"34","author":"Ingman","year":"2006","journal-title":"Nucleic Acids Res."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Attimonelli, M., Accetturo, M., Santamaria, M., Lascaro, D., Scioscia, G., Pappada, G., Russo, L., Zanchetta, L., and Tommaseo-Ponzetta, M. (2005). HmtDB, a human mitochondrial genomic resource based on variability studies supporting population genetics and biomedical research. BMC Bioinformatics.","DOI":"10.1186\/1471-2105-6-S4-S4"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2744","DOI":"10.1093\/bioinformatics\/btp528","article-title":"Automated inference of molecular mechanisms of disease from amino acid substitutions","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"ref_31","unstructured":"Pejaver, V., Urresti, J., Lugo-Martinez, J., Pagel, K.A., Lin, G.N., Nam, H., Mort, M., Cooper, D.N., Sebat, J., and Iakoucheva, L.M. MutPred2: Inferring the molecular and phenotypic impact of amino acid variants. bioRxiv, 134981."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/nmeth0410-248","article-title":"A method and server for predicting damaging missense mutations","volume":"7","author":"Adzhubei","year":"2010","journal-title":"Nat. Methods"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e46688","DOI":"10.1371\/journal.pone.0046688","article-title":"Predicting the functional effect of amino acid substitutions and indels","volume":"7","author":"Choi","year":"2012","journal-title":"PLoS ONE"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1038\/nprot.2009.86","article-title":"Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm","volume":"4","author":"Kumar","year":"2009","journal-title":"Nat. Protoc."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1196\/annals.1427.001","article-title":"A mitochondrial etiology of neurodegenerative diseases: Evidence from Parkinson\u2019s disease","volume":"1147","author":"Khusnutdinova","year":"2008","journal-title":"Ann. NY Acad. Sci."},{"key":"ref_36","first-page":"1218","article-title":"A variant of Leber hereditary optic neuropathy characterized by recovery of vision and by an unusual mitochondrial genetic etiology","volume":"51","author":"Mackey","year":"1992","journal-title":"Am. J. Hum. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4211","DOI":"10.1167\/iovs.06-0295","article-title":"Mitochondrial abnormalities in patients with LHON-like optic neuropathies","volume":"47","author":"Bosley","year":"2006","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1002\/humu.22023","article-title":"Novel mitochondrial DNA mutations responsible for maternally inherited nonsyndromic hearing loss","volume":"33","author":"Pertuiset","year":"2012","journal-title":"Hum. Mutat."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1460","DOI":"10.1086\/375537","article-title":"Sequence analysis of the mitochondrial genomes from Dutch pedigrees with Leber hereditary optic neuropathy","volume":"72","author":"Howell","year":"2003","journal-title":"Am. J. Hum. Genet."},{"key":"ref_40","first-page":"2343","article-title":"Point mutations associated with Leber hereditary optic neuropathy in a Latvian population","volume":"19","author":"Aitullina","year":"2013","journal-title":"Mol. Vis."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1370","DOI":"10.1167\/iovs.15-18306","article-title":"Prevalence and Genetics of Leber Hereditary Optic Neuropathy in the Danish Population","volume":"57","author":"Rosenberg","year":"2016","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/j.survophthal.2009.10.002","article-title":"The neuro-ophthalmology of mitochondrial disease","volume":"55","author":"Fraser","year":"2010","journal-title":"Surv. Ophthalmol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.mito.2008.08.002","article-title":"A family with 3460G>A and 11778G>A mutations and haplogroup analysis of Polish Leber hereditary optic neuropathy patients","volume":"5-6","author":"Tonska","year":"2008","journal-title":"Mitochondrion"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.mito.2016.10.002","article-title":"Characterization of a Leber\u2019s hereditary optic neuropathy (LHON) family harboring two primary LHON mutations m.11778G>A and m.14484T>C of the mitochondrial DNA","volume":"36","author":"Catarino","year":"2016","journal-title":"Mitochondrion"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1136\/bjophthalmol-2013-304140","article-title":"ND4L gene concurrent 10609T>C and 10663T>C mutations are associated with Leber\u2019s hereditary optic neuropathy in a large pedigree from Kuwait","volume":"98","author":"Behbehani","year":"2014","journal-title":"Br. J. Ophthalmol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Achilli, A., Iommarini, L., Olivieri, A., Pala, M., Hooshiar Kashani, B., Reynier, P., La Morgia, C., Valentino, L.M., Liguori, R., and Pizza, F. (2012). Rare primary mitochondrial DNA mutations and probable synergistic variants in Leber\u2019s hereditary optic neuropathy. PLoS One, 7.","DOI":"10.1371\/journal.pone.0042242"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1017\/cjn.2015.345","article-title":"Co-existence of m.10663T>C Mutation with Haplogroup L3f1b Background in a Patient with LHON","volume":"43","author":"Kondkar","year":"2016","journal-title":"Can. J. Neurol. Sci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.bbrc.2009.05.127","article-title":"Confirmation of the mitochondrial ND1 gene mutation G3635A as a primary LHON mutation","volume":"386","author":"Yang","year":"2006","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_49","first-page":"3087","article-title":"Complete mitochondrial DNA genome sequence variation of Chinese families with mutation m.3635G>A and Leber hereditary optic neuropathy","volume":"18","author":"Bi","year":"2012","journal-title":"Mol. Vis."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1086\/519394","article-title":"Clinical expression of Leber hereditary optic neuropathy is affected by the mitochondrial DNA-haplogroup background","volume":"81","author":"Hudson","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Ghelli, A., Porcelli, A.M., Zanna, C., Vidoni, S., Mattioli, S., Barbieri, A., Iommarini, L., Pala, M., Achilli, A., and Torroni, A. (2009). The background of mitochondrial DNA haplogroup J increases the sensitivity of Leber\u2019s hereditary optic neuropathy cells to 2,5-hexanedione toxicity. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0007922"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.gene.2005.05.001","article-title":"The mitochondrial genome in human adaptive radiation and disease: On road to therapeutics and performance enhancement","volume":"354","author":"Wallace","year":"2005","journal-title":"Gene"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.cell.2015.08.067","article-title":"Mitochondrial DNA Variation in Human Radiation and Disease","volume":"163","author":"Wallace","year":"2015","journal-title":"Cell"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1136\/jmedgenet-2013-101818","article-title":"The novel mitochondrial 16S rRNA 2336T>C mutation is associated with hypertrophic cardiomyopathy","volume":"51","author":"Lui","year":"2014","journal-title":"J. Med. Genet."},{"key":"ref_55","first-page":"214","article-title":"Future of human mitochondrial DNA editing technologies","volume":"30","author":"Verechshagina","year":"2019","journal-title":"Mitochondrial DNA A DNA Mapp. Seq. Anal."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/8\/12\/1574\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:40:16Z","timestamp":1760190016000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/8\/12\/1574"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,4]]},"references-count":55,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["cells8121574"],"URL":"https:\/\/doi.org\/10.3390\/cells8121574","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/744219","asserted-by":"object"}]},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,4]]}}}