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Publication

A Wars2 Mutant Mouse Model Displays OXPHOS Deficiencies and Activation of Tissue-Specific Stress Response Pathways.

Cell reports | 2018

Mutations in genes essential for mitochondrial function have pleiotropic effects. The mechanisms underlying these traits yield insights into metabolic homeostasis and potential therapies. Here we report the characterization of a mouse model harboring a mutation in the tryptophanyl-tRNA synthetase 2 (Wars2) gene, encoding the mitochondrial-localized WARS2 protein. This hypomorphic allele causes progressive tissue-specific pathologies, including hearing loss, reduced adiposity, adipose tissue dysfunction, and hypertrophic cardiomyopathy. We demonstrate the tissue heterogeneity arises as a result of variable activation of the integrated stress response (ISR) pathway and the ability of certain tissues to respond to impaired mitochondrial translation. Many of the systemic metabolic effects are likely mediated through elevated fibroblast growth factor 21 (FGF21) following activation of the ISR in certain tissues. These findings demonstrate the potential pleiotropy associated with Wars2 mutations in patients.

Pubmed ID: 30566859 RIS Download

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Associated grants

Agency: Medical Research Council, United Kingdom
Id: MC_U142684175
Agency: Medical Research Council, United Kingdom
Id: MC_UP_1503/2
Agency: Wellcome Trust, United Kingdom
Agency: Medical Research Council, United Kingdom
Id: MC_U142661184
Agency: Medical Research Council, United Kingdom
Id: MC_UP_1502/1
Agency: Medical Research Council, United Kingdom
Id: MR/J010448/1

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International Mouse Phenotyping Consortium (IMPC) (tool)

RRID:SCR_006158

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RRID:SCR_001876

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RRID:SCR_003202

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RRID:SCR_005375

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RRID:SCR_008392

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RRID:SCR_012931

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