{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T19:51:47Z","timestamp":1767383507138,"version":"3.40.5"},"reference-count":44,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2023,9,27]],"date-time":"2023-09-27T00:00:00Z","timestamp":1695772800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of health","award":["RO1AG059683"],"award-info":[{"award-number":["RO1AG059683"]}]},{"name":"National institute of health","award":["R21NS134144"],"award-info":[{"award-number":["R21NS134144"]}]},{"name":"National Institute of health","award":["2T32HL120822"],"award-info":[{"award-number":["2T32HL120822"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Barth Syndrome is a rare, X-linked disorder caused by mutation of the gene <jats:italic>TAFAZZIN<\/jats:italic> (<jats:italic>TAZ<\/jats:italic>). The corresponding Tafazzin protein is involved in the remodeling of cardiolipin, a phospholipid with critical roles in mitochondrial function. While recent clinical trials have been promising, there is still no cure for Barth Syndrome. Because <jats:italic>TAZ<\/jats:italic> is highly conserved, multiple animal and cell culture models exist for pre-clinical testing of therapeutics. However, since the same mutation in different patients can lead to different symptoms and responses to treatment, isogenized experimental models can\u2019t fully account for human disease conditions. On the other hand, isogenized animal models allow for sufficient numbers to thoroughly establish efficacy for a given genetic background. Therefore, a combined method for testing treatments in a panel of isogenized cohorts that are genetically distinct from each other would be transformative for testing emerging pre-clinical therapies. To aid in this effort, we\u2019ve created a novel panel of 10 <jats:italic>Drosophila<\/jats:italic> lines, each with the same <jats:italic>TAZ<\/jats:italic> mutation in highly diverse genetic backgrounds, to serve as a helpful resource to represent natural variation in background genetics in pre-clinical studies. As a proof of principle, we test our panel here using nicotinamide riboside (NR), a treatment with established therapeutic value, to evaluate how robust this therapy is across the 10 genetic backgrounds in this novel reference panel. We find substantial variation in the response to NR across backgrounds. We expect this resource will be valuable in pre-clinical testing of emerging therapies for Barth Syndrome.<\/jats:p>","DOI":"10.1371\/journal.pone.0286380","type":"journal-article","created":{"date-parts":[[2023,9,27]],"date-time":"2023-09-27T17:34:56Z","timestamp":1695836096000},"page":"e0286380","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["A novel panel of Drosophila TAFAZZIN mutants in distinct genetic backgrounds as a resource for therapeutic testing"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9146-8017","authenticated-orcid":true,"given":"Kristin","family":"Richardson","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4516-3183","authenticated-orcid":true,"given":"Robert","family":"Wessells","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2023,9,27]]},"reference":[{"issue":"1","key":"pone.0286380.ref001","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1002\/jimd.12422","article-title":"Clinical presentation and natural history of Barth Syndrome: An overview","volume":"45","author":"C Taylor","year":"2022","journal-title":"J Inherit Metab Dis"},{"issue":"4","key":"pone.0286380.ref002","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1038\/ng0496-385","article-title":"A novel X-linked gene, G4.5. is responsible for Barth syndrome","volume":"12","author":"S, D Bione","year":"1996","journal-title":"Nat Genet"},{"issue":"3","key":"pone.0286380.ref003","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1093\/hmg\/dds447","article-title":"Seven functional classes of Barth syndrome mutation","volume":"22","author":"K Whited","year":"2013","journal-title":"Hum Mol Genet"},{"issue":"4","key":"pone.0286380.ref004","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1002\/ajmg.a.30661","article-title":"Barth syndrome: TAZ gene mutations, mRNAs, and evolution","volume":"134","author":"IL Gonzalez","year":"2005","journal-title":"Am J Med Genet A"},{"issue":"1","key":"pone.0286380.ref005","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.ymgme.2013.11.006","article-title":"Tafazzin splice variants and mutations in Barth syndrome","volume":"111","author":"SM Kirwin","year":"2014","journal-title":"Mol Genet Metab"},{"issue":"10","key":"pone.0286380.ref006","doi-asserted-by":"crossref","first-page":"2003","DOI":"10.1016\/j.bbamem.2009.07.009","article-title":"The enigmatic role of tafazzin in cardiolipin metabolism","volume":"1788","author":"RH Houtkooper","year":"2009","journal-title":"Biochim Biophys Acta"},{"issue":"3","key":"pone.0286380.ref007","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1083\/jcb.201008177","article-title":"Barth syndrome mutations that cause tafazzin complex lability","volume":"192","author":"SM Claypool","year":"2011","journal-title":"J Cell Biol"},{"issue":"42","key":"pone.0286380.ref008","doi-asserted-by":"crossref","first-page":"29230","DOI":"10.1074\/jbc.M109.016642","article-title":"Characterization of tafazzin splice variants from humans and fruit flies","volume":"284","author":"Y Xu","year":"2009","journal-title":"J Biol Chem"},{"issue":"43","key":"pone.0286380.ref009","doi-asserted-by":"crossref","first-page":"44394","DOI":"10.1074\/jbc.M405479200","article-title":"The human TAZ gene complements mitochondrial dysfunction in the yeast taz1Delta mutant. Implications for Barth syndrome","volume":"279","author":"L Ma","year":"2004","journal-title":"J Biol Chem"},{"issue":"16","key":"pone.0286380.ref010","doi-asserted-by":"crossref","first-page":"2493","DOI":"10.1007\/s00018-008-8030-5","article-title":"Cardiolipin, the heart of mitochondrial metabolism","volume":"65","author":"RH Houtkooper","year":"2008","journal-title":"Cell Mol Life Sci"},{"issue":"4","key":"pone.0286380.ref011","doi-asserted-by":"crossref","first-page":"1874","DOI":"10.1016\/S0021-9258(19)69888-1","article-title":"Cardiolipin requirement for electron transfer in complex I and III of the mitochondrial respiratory chain","volume":"256","author":"M Fry","year":"1981","journal-title":"J Biol Chem"},{"issue":"3","key":"pone.0286380.ref012","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1007\/s00431-011-1597-0","article-title":"Differing clinical courses and outcomes in two siblings with Barth syndrome and left ventricular noncompaction","volume":"171","author":"N Momoi","year":"2012","journal-title":"Eur J Pediatr"},{"issue":"1","key":"pone.0286380.ref013","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1002\/jimd.12423","article-title":"Experimental models of Barth syndrome","volume":"45","author":"WT Pu","year":"2022","journal-title":"J Inherit Metab Dis"},{"issue":"5","key":"pone.0286380.ref014","doi-asserted-by":"crossref","first-page":"e22533","DOI":"10.2196\/22533","article-title":"Treatment of Barth Syndrome by Cardiolipin Manipulation (CARDIOMAN) With Bezafibrate: Protocol for a Randomized Placebo-Controlled Pilot Trial Conducted in the Nationally Commissioned Barth Syndrome Service.","volume":"10","author":"L Dabner","year":"2021","journal-title":"JMIR Res Protoc."},{"issue":"3","key":"pone.0286380.ref015","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1038\/s41436-020-01006-8","article-title":"A phase 2\/3 randomized clinical trial followed by an open-label extension to evaluate the effectiveness of elamipretide in Barth syndrome, a genetic disorder of mitochondrial cardiolipin metabolism","volume":"23","author":"W Reid Thompson","year":"2021","journal-title":"Genet Med"},{"issue":"12","key":"pone.0286380.ref016","doi-asserted-by":"crossref","first-page":"1470","DOI":"10.1093\/gerona\/glv047","article-title":"Longevity GWAS Using the Drosophila Genetic Reference Panel","volume":"70","author":"DK Ivanov","year":"2015","journal-title":"J Gerontol A Biol Sci Med Sci"},{"issue":"4","key":"pone.0286380.ref017","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1534\/g3.119.401034","article-title":"Genetic Networks Underlying Natural Variation in Basal and Induced Activity Levels in Drosophila melanogaster.","volume":"10","author":"LP Watanabe","year":"2020","journal-title":"G3 (Bethesda)."},{"issue":"7384","key":"pone.0286380.ref018","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1038\/nature10811","article-title":"The Drosophila melanogaster Genetic Reference Panel","volume":"482","author":"TF Mackay","year":"2012","journal-title":"Nature"},{"issue":"31","key":"pone.0286380.ref019","doi-asserted-by":"crossref","first-page":"11584","DOI":"10.1073\/pnas.0603242103","article-title":"A Drosophila model of Barth syndrome","volume":"103","author":"Y Xu","year":"2006","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"10","key":"pone.0286380.ref020","doi-asserted-by":"crossref","DOI":"10.1242\/dmm.049279","article-title":"Stimulating the sir2-spargel axis rescues exercise capacity and mitochondrial respiration in a Drosophila model of Barth syndrome.","volume":"15","author":"D Damschroder","year":"2022","journal-title":"Dis Model Mech."},{"issue":"3","key":"pone.0286380.ref021","doi-asserted-by":"crossref","DOI":"10.14814\/phy2.13604","article-title":"Drosophila tafazzin mutants have impaired exercise capacity.","volume":"6","author":"D Damschroder","year":"2018","journal-title":"Physiol Rep."},{"issue":"4","key":"pone.0286380.ref022","doi-asserted-by":"crossref","first-page":"159094","DOI":"10.1016\/j.bbalip.2021.159094","article-title":"NAD supplementation improves mitochondrial performance of cardiolipin mutants","volume":"1867","author":"J Ji","year":"2022","journal-title":"Biochim Biophys Acta Mol Cell Biol Lipids"},{"issue":"Pt 18","key":"pone.0286380.ref023","article-title":"Variation in the response to exercise stimulation in Drosophila: marathon runner versus sprinter genotypes","volume":"223","author":"NC Riddle","year":"2020","journal-title":"J Exp Biol"},{"issue":"6","key":"pone.0286380.ref024","doi-asserted-by":"crossref","first-page":"e5886","DOI":"10.1371\/journal.pone.0005886","article-title":"Exercise-training in young Drosophila melanogaster reduces age-related decline in mobility and cardiac performance.","volume":"4","author":"N Piazza","year":"2009","journal-title":"PLoS One"},{"issue":"61","key":"pone.0286380.ref025","doi-asserted-by":"crossref","DOI":"10.3791\/3786-v","article-title":"Endurance training protocol and longitudinal performance assays for Drosophila melanogaster.","author":"MJ Tinkerhess","year":"2012","journal-title":"J Vis Exp."},{"issue":"1\u20134","key":"pone.0286380.ref026","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1080\/19336934.2020.1835329","article-title":"The effects of genetic background on exercise performance in Drosophila.","volume":"14","author":"D Damschroder","year":"2020","journal-title":"Fly (Austin)."},{"issue":"6","key":"pone.0286380.ref027","doi-asserted-by":"crossref","DOI":"10.3390\/nu12061616","article-title":"Nicotinamide Riboside-The Current State of Research and Therapeutic Uses.","volume":"12","author":"M Mehmel","year":"2020","journal-title":"Nutrients"},{"issue":"1","key":"pone.0286380.ref028","doi-asserted-by":"crossref","first-page":"9772","DOI":"10.1038\/s41598-019-46120-z","article-title":"Safety and Metabolism of Long-term Administration of NIAGEN (Nicotinamide Riboside Chloride) in a Randomized, Double-Blind, Placebo-controlled Clinical Trial of Healthy Overweight Adults.","volume":"9","author":"D Conze","year":"2019","journal-title":"Sci Rep."},{"issue":"1","key":"pone.0286380.ref029","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.1038\/s41467-018-03421-7","article-title":"Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD(+) in healthy middle-aged and older adults.","volume":"9","author":"CR Martens","year":"2018","journal-title":"Nat Commun"},{"issue":"11","key":"pone.0286380.ref030","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1177\/0960327115626254","article-title":"Safety assessment of nicotinamide riboside, a form of vitamin B(3).","volume":"35","author":"DB Conze","year":"2016","journal-title":"Hum Exp Toxicol"},{"issue":"18","key":"pone.0286380.ref031","doi-asserted-by":"crossref","first-page":"4413","DOI":"10.1113\/jphysiol.2011.212712","article-title":"Mitochondria: isolation, structure and function.","volume":"589","author":"M Picard","year":"2011","journal-title":"J Physiol."},{"issue":"6","key":"pone.0286380.ref032","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/j.tig.2013.01.009","article-title":"Does your gene need a background check? How genetic background impacts the analysis of mutations, genes, and evolution","volume":"29","author":"CH Chandler","year":"2013","journal-title":"Trends Genet"},{"issue":"1","key":"pone.0286380.ref033","doi-asserted-by":"crossref","first-page":"26","DOI":"10.2337\/diab.33.1.26","article-title":"Effect of genetic background on the therapeutic effects of dehydroepiandrosterone (DHEA) in diabetes-obesity mutants and in aged normal mice.","volume":"33","author":"DL Coleman","year":"1984","journal-title":"Diabetes"},{"key":"pone.0286380.ref034","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.parkreldis.2018.08.006","article-title":"Genetic background and outcome of Deep Brain Stimulation in Parkinson\u2019s disease","volume":"64","author":"MG Rizzone","year":"2019","journal-title":"Parkinsonism Relat Disord"},{"issue":"20","key":"pone.0286380.ref035","first-page":"4494","article-title":"Effect of genetic background on the phenotype of the Smn2B\/- mouse model of spinal muscular atrophy","volume":"25","author":"M Eshraghi","year":"2016","journal-title":"Hum Mol Genet"},{"issue":"2","key":"pone.0286380.ref036","doi-asserted-by":"crossref","first-page":"79","DOI":"10.3109\/17482968.2010.550626","article-title":"Effect of genetic background on phenotype variability in transgenic mouse models of amyotrophic lateral sclerosis: a window of opportunity in the search for genetic modifiers.","volume":"12","author":"TD Heiman-Patterson","year":"2011","journal-title":"Amyotroph Lateral Scler"},{"key":"pone.0286380.ref037","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/B978-0-444-53497-2.00010-3","article-title":"Clinical outcome of deep brain stimulation for Parkinson\u2019s disease","volume":"116","author":"G Deuschl","year":"2013","journal-title":"Handb Clin Neurol"},{"issue":"13","key":"pone.0286380.ref038","doi-asserted-by":"crossref","first-page":"2327","DOI":"10.1002\/mds.23903","article-title":"Beyond nine years of continuous subthalamic nucleus deep brain stimulation in Parkinson\u2019s disease","volume":"26","author":"M Zibetti","year":"2011","journal-title":"Mov Disord"},{"issue":"1","key":"pone.0286380.ref039","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.kint.2022.03.020","article-title":"The impact of genetic background on mouse models of kidney disease","volume":"102","author":"R Bufi","year":"2022","journal-title":"Kidney Int"},{"issue":"1","key":"pone.0286380.ref040","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.ajhg.2011.11.029","article-title":"Five years of GWAS discovery","volume":"90","author":"PM Visscher","year":"2012","journal-title":"Am J Hum Genet"},{"issue":"3","key":"pone.0286380.ref041","doi-asserted-by":"crossref","DOI":"10.3390\/genes11030239","article-title":"Genetic Modifiers and Rare Mendelian Disease.","volume":"11","author":"K Rahit","year":"2020","journal-title":"Genes (Basel)."},{"issue":"19","key":"pone.0286380.ref042","doi-asserted-by":"crossref","DOI":"10.21769\/BioProtoc.3037","article-title":"Drosophila Endurance Training and Assessment of Its Effects on Systemic Adaptations.","volume":"8","author":"D Damschroder","year":"2018","journal-title":"Bio-Protocol."},{"issue":"6","key":"pone.0286380.ref043","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1111\/j.1474-9726.2012.00864.x","article-title":"dFatp regulates nutrient distribution and long-term physiology in Drosophila.","volume":"11","author":"A Sujkowski","year":"2012","journal-title":"Aging Cell"},{"issue":"6","key":"pone.0286380.ref044","doi-asserted-by":"crossref","first-page":"e6063","DOI":"10.1371\/journal.pone.0006063","article-title":"Quantification of food intake in Drosophila.","volume":"4","author":"R Wong","year":"2009","journal-title":"PLoS One."}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0286380","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,27]],"date-time":"2023-09-27T17:35:28Z","timestamp":1695836128000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0286380"}},"subtitle":[],"editor":[{"given":"Giovanni","family":"Messina","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2023,9,27]]},"references-count":44,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2023,9,27]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0286380","relation":{},"ISSN":["1932-6203"],"issn-type":[{"type":"electronic","value":"1932-6203"}],"subject":[],"published":{"date-parts":[[2023,9,27]]}}}