{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T02:30:00Z","timestamp":1792895400729,"version":"4.5.0"},"reference-count":45,"publisher":"Oxford University Press (OUP)","issue":"13","license":[{"start":{"date-parts":[[2017,4,18]],"date-time":"2017-04-18T00:00:00Z","timestamp":1492473600000},"content-version":"vor","delay-in-days":1,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004359","name":"Swedish Research Council","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Stockholm County Council"},{"name":"A.We."},{"name":"Swedish Foundation for Strategic Research"},{"name":"Knut & Alice Wallenberg Foundation"},{"DOI":"10.13039\/100012538","name":"The Swedish Cancer Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100012538","id-type":"DOI","asserted-by":"crossref"}]},{"name":"The Swedish Brain Foundation"},{"DOI":"10.13039\/501100004359","name":"Swedish Research Council","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Mutations in the mitochondrial DNA polymerase, POLG, are associated with a variety of clinical presentations, ranging from early onset fatal brain disease in Alpers syndrome to chronic progressive external ophthalmoplegia. The majority of mutations are linked with disturbances of mitochondrial DNA (mtDNA) integrity and maintenance. On a molecular level, depending on their location within the enzyme, mutations either lead to mtDNA depletion or the accumulation of multiple mtDNA deletions, and in some cases these molecular changes can be correlated to the clinical presentation. We identified a patient with a dominant p.Y955H mutation in POLG, presenting with a severe, early-onset multi-systemic mitochondrial disease with bilateral sensorineural hearing loss, cataract, myopathy, and liver failure. Using a combination of disease models of Drosophila melanogaster and in vitro biochemistry analysis, we compare the molecular consequences of the p.Y955H mutation to the well-documented p.Y955C mutation. We demonstrate that both mutations affect mtDNA replication and display a dominant negative effect, with the p.Y955H allele resulting in a more severe polymerase dysfunction.<\/jats:p>","DOI":"10.1093\/hmg\/ddx146","type":"journal-article","created":{"date-parts":[[2017,4,14]],"date-time":"2017-04-14T19:08:18Z","timestamp":1492196898000},"page":"2515-2525","source":"Crossref","is-referenced-by-count":20,"title":["A multi-systemic mitochondrial disorder due to a dominant p.Y955H disease variant in DNA polymerase gamma"],"prefix":"10.1093","volume":"26","author":[{"given":"Triinu","family":"Siibak","sequence":"first","affiliation":[{"name":"1Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Gothenburg SE-405\u200930, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Clemente","sequence":"additional","affiliation":[{"name":"2Max Planck Institute Biology of Ageing - Karolinska Institutet Laboratory, Division of Metabolic Diseases, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, SE-171 77, Sweden,"},{"name":"3Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm SE-171\u200977, Sweden,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Bratic","sequence":"additional","affiliation":[{"name":"4Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Cologne D-50931, Germany,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helene","family":"Bruhn","sequence":"additional","affiliation":[{"name":"3Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm SE-171\u200977, Sweden,"},{"name":"5Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm SE-171\u200976, Sweden,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timo E.S.","family":"Kauppila","sequence":"additional","affiliation":[{"name":"4Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Cologne D-50931, Germany,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bertil","family":"Macao","sequence":"additional","affiliation":[{"name":"1Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Gothenburg SE-405\u200930, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian A.","family":"Rosenberger","sequence":"additional","affiliation":[{"name":"2Max Planck Institute Biology of Ageing - Karolinska Institutet Laboratory, Division of Metabolic Diseases, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, SE-171 77, Sweden,"},{"name":"3Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm SE-171\u200977, Sweden,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Lesko","sequence":"additional","affiliation":[{"name":"3Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm SE-171\u200977, Sweden,"},{"name":"5Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm SE-171\u200976, Sweden,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rolf","family":"Wibom","sequence":"additional","affiliation":[{"name":"3Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm SE-171\u200977, Sweden,"},{"name":"5Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm SE-171\u200976, Sweden,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"Naess","sequence":"additional","affiliation":[{"name":"3Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm SE-171\u200977, Sweden,"},{"name":"5Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm SE-171\u200976, Sweden,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inger","family":"Nennesmo","sequence":"additional","affiliation":[{"name":"6Department of Pathology, Karolinska University Hospital, SE-171\u200977 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Wedell","sequence":"additional","affiliation":[{"name":"2Max Planck Institute Biology of Ageing - Karolinska Institutet Laboratory, Division of Metabolic Diseases, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, SE-171 77, Sweden,"},{"name":"5Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm SE-171\u200976, Sweden,"},{"name":"7Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm SE-171\u200976, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley","family":"Peter","sequence":"additional","affiliation":[{"name":"1Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Gothenburg SE-405\u200930, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Freyer","sequence":"additional","affiliation":[{"name":"2Max Planck Institute Biology of Ageing - Karolinska Institutet Laboratory, Division of Metabolic Diseases, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, SE-171 77, Sweden,"},{"name":"3Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm SE-171\u200977, Sweden,"},{"name":"5Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm SE-171\u200976, Sweden,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Falkenberg","sequence":"additional","affiliation":[{"name":"1Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Gothenburg SE-405\u200930, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Wredenberg","sequence":"additional","affiliation":[{"name":"2Max Planck Institute Biology of Ageing - 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