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Genetic modifiers modulate phenotypic expression of tafazzin deficiency in a mouse model of Barth syndrome

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机构: [1]Department of Cardiology, Boston Children's Hospital, Boston, MA, USA. [2]Division of Newborn Medicine, Boston Children's Hospital, Boston, MA, USA. [3]Department of Pharmacology, Sichuan University West China School of Basic Sciences and Forensic Medicine, Chengdu, Sichuan, China. [4]Department of Anesthesiology, New York University School of Medicine, New York, NY, USA. [5]Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. [6]Transgenic Technology Laboratory, Cancer Research UK Beatson Institute, Glasgow, UK.
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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 8 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.© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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出版当年[2023]版:
大类 | 2 区 生物学
小类 | 3 区 生化与分子生物学 3 区 遗传学
最新[2023]版:
大类 | 2 区 生物学
小类 | 3 区 生化与分子生物学 3 区 遗传学
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第一作者机构: [1]Department of Cardiology, Boston Children's Hospital, Boston, MA, USA.
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通讯机构: [1]Department of Cardiology, Boston Children's Hospital, Boston, MA, USA. [6]Transgenic Technology Laboratory, Cancer Research UK Beatson Institute, Glasgow, UK.
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