{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T09:46:12Z","timestamp":1779183972217,"version":"3.51.4"},"reference-count":38,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2021,9,30]],"date-time":"2021-09-30T00:00:00Z","timestamp":1632960000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32-GM008629"],"award-info":[{"award-number":["T32-GM008629"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32-GM007337"],"award-info":[{"award-number":["T32-GM007337"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30-EY025580"],"award-info":[{"award-number":["P30-EY025580"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,3,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The m.3243A&amp;gt;G mutation in the mitochondrial genome commonly causes retinal degeneration in patients with maternally inherited diabetes and deafness and mitochondrial encephalopathy, lactic acidosis and stroke-like episodes. Like other mitochondrial mutations, m.3243A&amp;gt;G is inherited from the mother with a variable proportion of wild type and mutant mitochondrial genomes in different cells. The mechanism by which the m.3243A&amp;gt;G variant in each tissue relates to the manifestation of disease phenotype is not fully understood. Using a digital PCR assay, we found that the % m.3243G in skin derived dermal fibroblasts was positively correlated with that of blood from the same individual. The % m.3243G detected in fibroblast cultures remained constant over multiple passages and was negatively correlated with mtDNA copy number. Although the % m.3243G present in blood was not correlated with severity of vision loss, as quantified by Goldmann visual field, a significant negative correlation between % m.3243G and the age of onset of visual symptoms was detected. Altogether, these results indicate that precise measurement of % m.3243G in clinically accessible tissues such as skin and blood may yield information relevant to the management of retinal m.3243A&amp;gt;G-associated disease.<\/jats:p>","DOI":"10.1093\/hmg\/ddab289","type":"journal-article","created":{"date-parts":[[2021,9,30]],"date-time":"2021-09-30T11:13:50Z","timestamp":1633000430000},"page":"775-782","source":"Crossref","is-referenced-by-count":4,"title":["Sensitive quantification of m.3243A&amp;gt;G mutational proportion in non-retinal tissues and its relationship with visual symptoms"],"prefix":"10.1093","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4320-2852","authenticated-orcid":false,"given":"Nathaniel K","family":"Mullin","sequence":"first","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, University of Iowa Institute for Vision Research, Iowa City, IA 52242, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristin R","family":"Anfinson","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, University of Iowa Institute for Vision Research, Iowa City, IA 52242, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Megan J","family":"Riker","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, University of Iowa Institute for Vision Research, Iowa City, IA 52242, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelsey L","family":"Wieland","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, University of Iowa Institute for Vision Research, Iowa City, IA 52242, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole J","family":"Tatro","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, University of Iowa Institute for Vision Research, Iowa City, IA 52242, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Todd E","family":"Scheetz","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, University of Iowa Institute for Vision Research, Iowa City, IA 52242, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert F","family":"Mullins","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, University of Iowa Institute for Vision Research, Iowa City, IA 52242, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edwin M","family":"Stone","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, University of Iowa Institute for Vision Research, Iowa City, IA 52242, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Budd A","family":"Tucker","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, University of Iowa Institute for Vision Research, Iowa City, IA 52242, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2021,9,30]]},"reference":[{"key":"2022030413201109100_ref1","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1038\/348651a0","article-title":"A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies","volume":"348","author":"Goto","year":"1990","journal-title":"Nature"},{"key":"2022030413201109100_ref2","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/0022-510X(93)90219-O","article-title":"Mitochondrial DNA mutations at nucleotide positions 3243 and 3271 in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes: a comparative study","volume":"115","author":"Sakuta","year":"1993","journal-title":"J. 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Neurol."},{"key":"2022030413201109100_ref31","doi-asserted-by":"crossref","first-page":"116562","DOI":"10.1016\/j.jns.2019.116562","article-title":"Heteroplasmy and phenotype spectrum of the mitochondrial tRNA(Leu (UUR)) gene m.3243A&gt;G mutation in seven Han Chinese families","volume":"408","author":"Liu","year":"2020","journal-title":"J. Neurol. Sci."},{"key":"2022030413201109100_ref32","article-title":"Heteroplasmy and copy number in the common m.3243A&gt;G mutation-a post-mortem genotype-phenotype analysis","volume":"11","author":"Scholle","year":"2020","journal-title":"Genes (Basel)"},{"key":"2022030413201109100_ref33","doi-asserted-by":"crossref","first-page":"16","DOI":"10.5966\/sctm.2012-0040","article-title":"Use of a synthetic xeno-free culture substrate for induced pluripotent stem cell induction and retinal differentiation","volume":"2","author":"Tucker","year":"2013","journal-title":"Stem Cells Transl. Med."},{"key":"2022030413201109100_ref34","doi-asserted-by":"crossref","first-page":"3372","DOI":"10.1167\/iovs.06-0868","article-title":"Differential macular and peripheral expression of bestrophin in human eyes and its implication for best disease","volume":"48","author":"Mullins","year":"2007","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"2022030413201109100_ref35","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1097\/IAE.0b013e3182483361","article-title":"Validation of tablet-based evaluation of color fundus images","volume":"32","author":"Christopher","year":"2012","journal-title":"Retina"},{"key":"2022030413201109100_ref36","volume-title":"Perimetry with and without Automation","author":"Anderson","year":"1987"},{"key":"2022030413201109100_ref37","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/0002-9394(86)90648-3","article-title":"Computerized quantitative analysis of kinetic visual fields","volume":"101","author":"Weleber","year":"1986","journal-title":"Am J. Ophthalmol."},{"key":"2022030413201109100_ref38","doi-asserted-by":"crossref","first-page":"535","DOI":"10.2147\/OPTH.S18815","article-title":"Volume of visual field assessed with kinetic perimetry and its application to static perimetry","volume":"5","author":"Christoforidis","year":"2011","journal-title":"Clin. 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