{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T22:24:46Z","timestamp":1792794286757,"version":"4.5.0"},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2023,3,14]],"date-time":"2023-03-14T00:00:00Z","timestamp":1678752000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","award":["W81XWH2110445"],"award-info":[{"award-number":["W81XWH2110445"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HL128694"],"award-info":[{"award-number":["R01HL128694"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100002651","name":"Barth Syndrome Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100002651","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Boston Children\u2019s Hospital Department of Cardiology","id":[{"id":"https:\/\/ror.org\/00dvg7y05","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,6,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Barth syndrome is an X-linked disorder caused by loss-of-function mutations in Tafazzin (TAZ), an acyltransferase that catalyzes remodeling of cardiolipin, a signature phospholipid of the inner mitochondrial membrane. Patients develop cardiac and skeletal muscle weakness, growth delay and neutropenia, although phenotypic expression varies considerably between patients. Taz knockout mice recapitulate many of the hallmark features of the disease. We used mouse genetics to test the hypothesis that genetic modifiers alter the phenotypic manifestations of Taz inactivation. We crossed TazKO\/X females in the C57BL6\/J inbred strain to males from eight inbred strains and evaluated the phenotypes of first-generation (F1) TazKO\/Y progeny, compared to TazWT\/Y littermates. We observed that genetic background strongly impacted phenotypic expression. C57BL6\/J and CAST\/EiJ[F1] TazKO\/Y mice developed severe cardiomyopathy, whereas A\/J[F1] TazKO\/Y mice had normal heart function. C57BL6\/J and WSB\/EiJ[F1] TazKO\/Y mice had severely reduced treadmill endurance, whereas endurance was normal in A\/J[F1] and CAST\/EiJ[F1] TazKO\/Y mice. In all genetic backgrounds, cardiolipin showed similar abnormalities in knockout mice, and transcriptomic and metabolomic investigations identified signatures of mitochondrial uncoupling and activation of the integrated stress response. TazKO\/Y cardiac mitochondria were small, clustered and had reduced cristae density in knockouts in severely affected genetic backgrounds but were relatively preserved in the permissive A\/J[F1] strain. Gene expression and mitophagy measurements were consistent with reduced mitophagy in knockout mice in genetic backgrounds intolerant of Taz mutation. Our data demonstrate that genetic modifiers powerfully modulate phenotypic expression of Taz loss-of-function and act downstream of cardiolipin, possibly by altering mitochondrial quality control.<\/jats:p>","DOI":"10.1093\/hmg\/ddad041","type":"journal-article","created":{"date-parts":[[2023,3,13]],"date-time":"2023-03-13T13:21:03Z","timestamp":1678713663000},"page":"2055-2067","source":"Crossref","is-referenced-by-count":27,"title":["Genetic modifiers modulate phenotypic expression of tafazzin deficiency in a mouse model of Barth syndrome"],"prefix":"10.1093","volume":"32","author":[{"given":"Suya","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Cardiology, Boston Children\u2019s Hospital , Boston, MA 02215NYU 10016 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"Yazawa","sequence":"additional","affiliation":[{"name":"Division of Newborn Medicine, Boston Children\u2019s Hospital , Boston, MA 02215NYU 10016 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin M","family":"Keating","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Boston Children\u2019s Hospital , Boston, MA 02215NYU 10016 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil","family":"Mazumdar","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Boston Children\u2019s Hospital , Boston, MA 02215NYU 10016 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Hauschild","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Boston Children\u2019s Hospital , Boston, MA 02215NYU 10016 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Boston Children\u2019s Hospital , Boston, MA 02215NYU 10016 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyan","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Sichuan University West China School of Basic Sciences and Forensic Medicine , Chengdu, Sichuan , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, New York University School of Medicine , New York, NY , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Shi","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center , Boston, MA 02115 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas","family":"Strathdee","sequence":"additional","affiliation":[{"name":"Transgenic Technology Laboratory, Cancer Research UK Beatson Institute , Glasgow , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert E","family":"Gerszten","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center , Boston, MA 02115 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Schlame","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, New York University School of Medicine , New York, NY , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William T","family":"Pu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Boston Children\u2019s Hospital , Boston, MA 02215NYU 10016 , USA"},{"name":"Transgenic Technology Laboratory, Cancer Research UK Beatson Institute , Glasgow , UK"},{"name":"Harvard Stem Cell Institute, Harvard University , 02138 Beatson, Cambridge, MA G61 1BD , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,3,14]]},"reference":[{"key":"2024031400340322600_ref1","doi-asserted-by":"crossref","first-page":"39217","DOI":"10.1074\/jbc.M606100200","article-title":"The enzymatic function of tafazzin","volume":"281","author":"Xu","year":"2006","journal-title":"J. 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