{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T23:12:19Z","timestamp":1778022739829,"version":"3.51.4"},"reference-count":31,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T00:00:00Z","timestamp":1773964800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T00:00:00Z","timestamp":1778025600000},"content-version":"vor","delay-in-days":47,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"DOI":"10.13039\/501100002426","name":"Telethon Foundation","doi-asserted-by":"crossref","award":["GGP19287A"],"award-info":[{"award-number":["GGP19287A"]}],"id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003407","name":"Italian Ministry for University and Research","doi-asserted-by":"crossref","award":["COMP-HUB and COMP-R Initiatives"],"award-info":[{"award-number":["COMP-HUB and COMP-R Initiatives"]}],"id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Italian Ministry of University and Research","award":["PNRR-Young Researcher MSCA program"],"award-info":[{"award-number":["PNRR-Young Researcher MSCA program"]}]},{"name":"Fondazione Citt\u00e0 della Speranza","award":["IRP-StG-2024"],"award-info":[{"award-number":["IRP-StG-2024"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"DOI":"10.1038\/s41598-026-44913-7","type":"journal-article","created":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T06:43:22Z","timestamp":1773989002000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Progressive cognitive impairment and ventricular tachycardia in a boy with biallelic POLG variants and a de novo RYR2 variation"],"prefix":"10.1038","volume":"16","author":[{"given":"Valentina","family":"Fumini","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandru Ionut","family":"Gilea","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Tacchetto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leonardo","family":"Salviati","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Enrico","family":"Baruffini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mara","family":"Doimo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,3,20]]},"reference":[{"key":"44913_CR1","doi-asserted-by":"publisher","first-page":"1006","DOI":"10.1038\/s41431-024-01770-0","volume":"33","author":"A Puma","year":"2025","unstructured":"Puma, A. et al. Double trouble: a comprehensive study into unrelated genetic comorbidities in adult patients with Facioscapulohumeral Muscular Dystrophy Type I. Eur. J. Hum. Genet. EJHG. 33, 1006\u20131014 (2025).","journal-title":"Eur. J. Hum. Genet. EJHG"},{"key":"44913_CR2","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1038\/s41582-018-0101-0","volume":"15","author":"S Rahman","year":"2019","unstructured":"Rahman, S. & Copeland, W. C. POLG-related disorders and their neurological manifestations. Nat. Rev. Neurol. 15, 40\u201352 (2019).","journal-title":"Nat. Rev. Neurol."},{"key":"44913_CR3","doi-asserted-by":"publisher","first-page":"1113","DOI":"10.1016\/j.bbabio.2014.01.021","volume":"1837","author":"GA Farnum","year":"2014","unstructured":"Farnum, G. A., Nurminen, A. & Kaguni, L. S. Mapping 136 pathogenic mutations into functional modules in human DNA polymerase \u03b3 establishes predictive genotype-phenotype correlations for the complete spectrum of POLG syndromes. Biochim. Biophys. Acta. 1837, 1113\u20131121 (2014).","journal-title":"Biochim. Biophys. Acta"},{"key":"44913_CR4","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1002\/iub.2770","volume":"75","author":"AI Gilea","year":"2023","unstructured":"Gilea, A. I. et al. The Saccharomyces cerevisiae mitochondrial DNA polymerase and its contribution to the knowledge about human POLG-related disorders. IUBMB Life. 75, 983\u20131002 (2023).","journal-title":"IUBMB Life"},{"key":"44913_CR5","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1038\/415198a","volume":"415","author":"DM Bers","year":"2002","unstructured":"Bers, D. M. Cardiac excitation-contraction coupling. Nature 415, 198\u2013205 (2002).","journal-title":"Nature"},{"key":"44913_CR6","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1152\/physrev.00013.2002","volume":"82","author":"M Fill","year":"2002","unstructured":"Fill, M. & Copello, J. A. Ryanodine receptor calcium release channels. Physiol. Rev. 82, 893\u2013922 (2002).","journal-title":"Physiol. Rev."},{"key":"44913_CR7","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1161\/01.CIR.103.2.196","volume":"103","author":"SG Priori","year":"2001","unstructured":"Priori, S. G. et al. Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation 103, 196\u2013200 (2001).","journal-title":"Circulation"},{"key":"44913_CR8","doi-asserted-by":"publisher","first-page":"871","DOI":"10.1161\/CIRCRESAHA.110.226845","volume":"108","author":"SG Priori","year":"2011","unstructured":"Priori, S. G. & Chen, S. R. W. Inherited dysfunction of sarcoplasmic reticulum Ca2\u2009+\u2009handling and arrhythmogenesis. Circ. Res. 108, 871\u2013883 (2011).","journal-title":"Circ. Res."},{"key":"44913_CR9","doi-asserted-by":"publisher","first-page":"e0131517","DOI":"10.1371\/journal.pone.0131517","volume":"10","author":"S Ohno","year":"2015","unstructured":"Ohno, S., Hasegawa, K. & Horie, M. Gender Differences in the Inheritance Mode of RYR2 Mutations in Catecholaminergic Polymorphic Ventricular Tachycardia Patients. PloS One. 10, e0131517 (2015).","journal-title":"PloS One"},{"key":"44913_CR10","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1038\/ncpcardio0419","volume":"3","author":"M Yano","year":"2006","unstructured":"Yano, M., Yamamoto, T., Ikeda, Y. & Matsuzaki, M. Mechanisms of Disease: ryanodine receptor defects in heart failure and fatal arrhythmia. Nat. Clin. Pract. Cardiovasc. Med. 3, 43\u201352 (2006).","journal-title":"Nat. Clin. Pract. Cardiovasc. Med."},{"key":"44913_CR11","doi-asserted-by":"publisher","first-page":"1674","DOI":"10.1093\/brain\/awl088","volume":"129","author":"R Horvath","year":"2006","unstructured":"Horvath, R. et al. Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene. Brain J. Neurol. 129, 1674\u20131684 (2006).","journal-title":"Brain J. Neurol."},{"key":"44913_CR12","doi-asserted-by":"publisher","first-page":"4198","DOI":"10.1074\/jbc.M116.773341","volume":"292","author":"KL DeBalsi","year":"2017","unstructured":"DeBalsi, K. L., Longley, M. J., Hoff, K. E. & Copeland, W. C. Synergistic Effects of the in cis T251I and P587L Mitochondrial DNA Polymerase \u03b3 Disease Mutations. J. Biol. Chem. 292, 4198\u20134209 (2017).","journal-title":"J. Biol. Chem."},{"key":"44913_CR13","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1111\/pcn.12496","volume":"71","author":"T Kasahara","year":"2017","unstructured":"Kasahara, T. et al. Enrichment of deleterious variants of mitochondrial DNA polymerase gene (POLG1) in bipolar disorder. Psychiatry Clin. Neurosci. 71, 518\u2013529 (2017).","journal-title":"Psychiatry Clin. Neurosci."},{"key":"44913_CR14","doi-asserted-by":"publisher","first-page":"5970","DOI":"10.1074\/jbc.M113.526418","volume":"289","author":"Y Qian","year":"2014","unstructured":"Qian, Y., Kachroo, A. H., Yellman, C. M., Marcotte, E. M. & Johnson, K. A. Yeast cells expressing the human mitochondrial DNA polymerase reveal correlations between polymerase fidelity and human disease progression. J. Biol. Chem. 289, 5970\u20135985 (2014).","journal-title":"J. Biol. Chem."},{"key":"44913_CR15","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/j.mito.2014.11.003","volume":"20","author":"E Baruffini","year":"2015","unstructured":"Baruffini, E., Ferrari, J., Dallabona, C., Donnini, C. & Lodi, T. Polymorphisms in DNA polymerase \u03b3 affect the mtDNA stability and the NRTI-induced mitochondrial toxicity in Saccharomyces cerevisiae. Mitochondrion 20, 52\u201363 (2015).","journal-title":"Mitochondrion"},{"key":"44913_CR16","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1093\/hmg\/ddi454","volume":"15","author":"GR Stuart","year":"2006","unstructured":"Stuart, G. R., Santos, J. H., Strand, M. K., Van Houten, B. & Copeland, W. C. Mitochondrial and nuclear DNA defects in Saccharomyces cerevisiae with mutations in DNA polymerase gamma associated with progressive external ophthalmoplegia. Hum. Mol. Genet. 15, 363\u2013374 (2006).","journal-title":"Hum. Mol. Genet."},{"key":"44913_CR17","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1002\/yea.3445","volume":"37","author":"B Dujon","year":"2020","unstructured":"Dujon, B. Mitochondrial genetics revisited. Yeast Chichester Engl. 37, 191\u2013205 (2020).","journal-title":"Yeast Chichester Engl."},{"key":"44913_CR18","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1007\/BF00422114","volume":"16","author":"Z Cui","year":"1989","unstructured":"Cui, Z. & Mason, T. L. A single nucleotide substitution at the rib2 locus of the yeast mitochondrial gene for 21S rRNA confers resistance to erythromycin and cold-sensitive ribosome assembly. Curr. Genet. 16, 273\u2013279 (1989).","journal-title":"Curr. Genet."},{"key":"44913_CR19","doi-asserted-by":"publisher","first-page":"8313","DOI":"10.1093\/nar\/12.22.8313","volume":"12","author":"F Sor","year":"1984","unstructured":"Sor, F. & Fukuhara, H. Erythromycin and spiramycin resistance mutations of yeast mitochondria: nature of the rib2 locus in the large ribosomal RNA gene. Nucleic Acids Res. 12, 8313\u20138318 (1984).","journal-title":"Nucleic Acids Res."},{"key":"44913_CR20","doi-asserted-by":"publisher","first-page":"6571","DOI":"10.1093\/nar\/10.21.6571","volume":"10","author":"F Sor","year":"1982","unstructured":"Sor, F. & Fukuhara, H. Identification of two erythromycin resistance mutations in the mitochondrial gene coding for the large ribosomal RNA in yeast. Nucleic Acids Res. 10, 6571\u20136577 (1982).","journal-title":"Nucleic Acids Res."},{"key":"44913_CR21","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1016\/j.nmd.2015.01.004","volume":"25","author":"C Scuderi","year":"2015","unstructured":"Scuderi, C. et al. The in cis T251I and P587L POLG1 base changes: description of a new family and literature review. Neuromuscul. Disord NMD. 25, 333\u2013339 (2015).","journal-title":"Neuromuscul. Disord NMD"},{"key":"44913_CR22","doi-asserted-by":"publisher","first-page":"e013437","DOI":"10.1161\/CIRCEP.124.013437","volume":"18","author":"CY Miyake","year":"2025","unstructured":"Miyake, C. Y. et al. Intellectual and Neurodevelopmental Delays in Pediatric Catecholaminergic Polymorphic Ventricular Tachycardia: Distinct Characteristics and a More Malignant Neurocardiac Phenotype. Circ. Arrhythm. Electrophysiol. 18, e013437 (2025).","journal-title":"Circ. Arrhythm. Electrophysiol."},{"key":"44913_CR23","doi-asserted-by":"publisher","first-page":"9072","DOI":"10.1093\/nar\/gkr618","volume":"39","author":"L Euro","year":"2011","unstructured":"Euro, L., Farnum, G. A., Palin, E., Suomalainen, A. & Kaguni, L. S. Clustering of Alpers disease mutations and catalytic defects in biochemical variants reveal new features of molecular mechanism of the human mitochondrial replicase, Pol \u03b3. Nucleic Acids Res. 39, 9072\u20139084 (2011).","journal-title":"Nucleic Acids Res."},{"key":"44913_CR24","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1016\/j.mito.2018.11.004","volume":"47","author":"D Piekutowska-Abramczuk","year":"2019","unstructured":"Piekutowska-Abramczuk, D. et al. The frequency of mitochondrial polymerase gamma related disorders in a large Polish population cohort. Mitochondrion 47, 179\u2013187 (2019).","journal-title":"Mitochondrion"},{"key":"44913_CR25","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1016\/j.mito.2019.08.005","volume":"49","author":"CH Trasvi\u00f1a-Arenas","year":"2019","unstructured":"Trasvi\u00f1a-Arenas, C. H. et al. Amino and carboxy-terminal extensions of yeast mitochondrial DNA polymerase assemble both the polymerization and exonuclease active sites. Mitochondrion 49, 166\u2013177 (2019).","journal-title":"Mitochondrion"},{"key":"44913_CR26","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1038\/s41419-020-03359-z","volume":"12","author":"N Facchinello","year":"2021","unstructured":"Facchinello, N. et al. Efficient clofilium tosylate-mediated rescue of POLG-related disease phenotypes in zebrafish. Cell. Death Dis. 12, 100 (2021).","journal-title":"Cell. Death Dis."},{"key":"44913_CR27","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1093\/hmg\/ddv509","volume":"25","author":"L Pitayu","year":"2016","unstructured":"Pitayu, L. et al. Combined use of Saccharomyces cerevisiae, Caenorhabditis elegans and patient fibroblasts leads to the identification of clofilium tosylate as a potential therapeutic chemical against POLG-related diseases. Hum. Mol. Genet. 25, 715\u2013727 (2016).","journal-title":"Hum. Mol. Genet."},{"key":"44913_CR28","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1038\/s41586-025-08856-9","volume":"642","author":"S Valenzuela","year":"2025","unstructured":"Valenzuela, S. et al. Small molecules restore mutant mitochondrial DNA polymerase activity. Nature 642, 501\u2013507 (2025).","journal-title":"Nature"},{"key":"44913_CR29","doi-asserted-by":"publisher","first-page":"2846","DOI":"10.1093\/hmg\/ddl219","volume":"15","author":"E Baruffini","year":"2006","unstructured":"Baruffini, E. et al. Genetic and chemical rescue of the Saccharomyces cerevisiae phenotype induced by mitochondrial DNA polymerase mutations associated with progressive external ophthalmoplegia in humans. Hum. Mol. Genet. 15, 2846\u20132855 (2006).","journal-title":"Hum. Mol. Genet."},{"key":"44913_CR30","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1016\/S0076-6879(02)50957-5","volume":"350","author":"RD Gietz","year":"2002","unstructured":"Gietz, R. D. & Woods, R. A. Transformation of yeast by lithium acetate\/single-stranded carrier DNA\/polyethylene glycol method. Methods Enzymol. 350, 87\u201396 (2002).","journal-title":"Methods Enzymol."},{"key":"44913_CR31","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1016\/j.ymeth.2010.02.023","volume":"51","author":"E Baruffini","year":"2010","unstructured":"Baruffini, E., Ferrero, I. & Foury, F. In vivo analysis of mtDNA replication defects in yeast. Methods San Diego Calif. 51, 426\u2013436 (2010).","journal-title":"Methods San Diego Calif."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-44913-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-44913-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-44913-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T22:38:25Z","timestamp":1778020705000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-44913-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,20]]},"references-count":31,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["44913"],"URL":"https:\/\/doi.org\/10.1038\/s41598-026-44913-7","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,20]]},"assertion":[{"value":"21 August 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 March 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 March 2026","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"}},{"value":"Research protocols involving patients\u2019 DNA were approved by the Clinical Research Ethics Committee of the HCP Azienda Ospedale Universit\u00e0 of Padova, Padova, Italy (62199-15\/09\/2025). Informed consents to the genetic test and to the use of the data from the analysis for publication and research were obtained from all the participants or their legal guardians. All data has been anonymized. All procedures followed the tenets of the Declaration of Helsinki.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics declaration"}}],"article-number":"14289"}}