VARS2 Depletion Leads to Activation of the Integrated Stress Response and Disruptions in Mitochondrial Fatty Acid Oxidation

Kayvanpour, Elham; Wisdom, Michael J.; Lackner, Maximilian K.; Sedaghat‐Hamedani, Farbod; Boeckel, Jes‐Niels; Müller, Marion; Eghbalian, Rose; Dudek, Jan; Doroudgar, Shirin; Maack, Christoph; Frey, Norbert; Meder, Benjamin

doi:10.3390/ijms23137327

Cited by 7 publications

(9 citation statements)

References 38 publications

(61 reference statements)

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“…In the case of other significant associations, IBAS hints at potential biologically pivotal candidates in disease etiology. VARS2 , the most significant gene identified with association to CAD (excluding all previously annotated genes in DisGeNET) has been identified to cause heart failure in zebrafish models when knocked-out (Kayvanpour et al , 2022). Another significant gene, ENPP3 , has known cardiac-specific function and is downstream of NKX2-5 , a transcription factor associated with congenital heart disease (Barth et al , 2010).…”

Section: Resultsmentioning

confidence: 99%

IBAS: Interaction-bridged association studies discovering novel genes underlying complex traits

Kossinna,

Kumarapeli,

Zhang

2023

Preprint

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The contribution of genetic variants to a complex phenotype may be mediated by various forms of complicated interactions. Currently, the discovery of genetic variants underlying interaction is limited, partly due to that the real interaction patterns are diverse and unknown, whereas exhaustively examining all potential combinations confers the risk of overfitting and instability. We propose IBAS, Interaction-Bridged Association Study, a new model using statistical learning techniques to extract representations of interaction patterns in transcriptome data, which act as a mediator for the next genotype-phenotype association test. Using simulated perturbation experiments, it is demonstrated that IBAS is more robust to noise than similar mediation-based protocols replying on single-genes, i.e., transcriptome-wide association studies (TWAS). By applying IBAS to real genotype-phenotype and expression data, we reported additional genes underlying complex traits as well as their biological annotations. IBAS unlocks the power of integrating gene-gene interactions in association mapping without concerning overfitting and instability.

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Section: Resultsmentioning

confidence: 99%

IBAS: Interaction-bridged association studies discovering novel genes underlying complex traits

Kossinna,

Kumarapeli,

Zhang

2023

Preprint

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“…The zebrafish models include FARS2, 25,44 RARS2, 45 VARS2, 46 YARS2, 47 and WARS2 11 knockdowns, with phenotypes ranging from retarded embryonic development to brain hypoplasia, heart failure, and CNS and skeletal muscle involvement. Findings resembling those in mtARS mouse models have been reported in zebrafish models, including respiratory chain deficiency, ISR activation, and disrupted fatty acid oxidation 46 . Knockdowns and mutants in Drosophila melanogaster have been studied for FARS2, 48,49 MARS2, 50 SARS2 51 and WARS2 50 .…”

Section: Mouse and Other Animal Models Of Reduced Mtars Functionmentioning

confidence: 99%

“…Findings resembling those in mtARS mouse models have been reported in zebrafish models, including respiratory chain deficiency, ISR activation, and disrupted fatty acid oxidation. 46 Knockdowns and mutants in Drosophila melanogaster have been studied for FARS2, 48,49 MARS2, 50 SARS2 51 and WARS2. 50 The fly models have shown variably compromised developmental viability, motility, and tissue development and have had alterations in mitochondrial respiration, lactic acidosis and reactive oxygen species accumulation.…”

Section: Mouse and Other Animal Models Of Reduced Mtars Functionmentioning

confidence: 99%

“…Knockdowns of mtARSs have also been studied in other animal models, particularly in zebrafish and flies. The zebrafish models include FARS2, 25,44 RARS2, 45 VARS2, 46 YARS2, 47 and WARS2 11 knockdowns, with phenotypes ranging from retarded embryonic development to brain hypoplasia, heart failure, and CNS and skeletal muscle involvement. Findings resembling those in mtARS mouse models have been reported in zebrafish models, including respiratory chain deficiency, ISR activation, and disrupted fatty acid oxidation 46 .…”

Section: Mouse and Other Animal Models Of Reduced Mtars Functionmentioning

confidence: 99%

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Disease models of mitochondrial aminoacyl‐tRNA synthetase defects

Tyynismaa

2023

J of Inher Metab Disea

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Mitochondrial aminoacyl‐tRNA synthetases (mtARS) are enzymes critical for the first step of mitochondrial protein synthesis by charging mitochondrial tRNAs with their cognate amino acids. Pathogenic variants in all 19 nuclear mtARS genes are now recognized as causing recessive mitochondrial diseases. Most mtARS disorders affect the nervous system, but the phenotypes range from multisystem diseases to tissue‐specific manifestations. However, the mechanisms behind the tissue specificities are poorly understood, and challenges remain in obtaining accurate disease models for developing and testing treatments. Here, some of the currently existing disease models that have increased our understanding of mtARS defects are discussed.

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“…Morpholino knockdown of endogenous rars2 in zebrafish leads to underdevelopment and structural abnormalities within the brain, mirroring morphological defects induced by knockdown of the tsen54 gene that encodes tRNA-splicing endonuclease complex, which like RARS2, has been linked to pontocerebellar hypoplasia (PCH) in human patients ( Kasher et al, 2011 ). Transient knockdown of vars2 expression during zebrafish embryonic development causes cerebral oedema ( Kayvanpour et al, 2022 ), and homozygous knockout of yars2 disrupts development of the retina ( Jin et al, 2021 ). Knockdown of vars2 in zebrafish additionally causes heart failure ( Kayvanpour et al, 2022 ), and wars2 knockdown causes pericardial oedema, impaired angiogenesis, and cardiac contractile failure ( Wang et al, 2016 ).…”

Section: Animal Model Systems For Studying Recessive Ars Diseasesmentioning

confidence: 99%

Recessive aminoacyl-tRNA synthetase disorders: lessons learned from in vivo disease models

et al. 2023

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Protein synthesis is a fundamental process that underpins almost every aspect of cellular functioning. Intriguingly, despite their common function, recessive mutations in aminoacyl-tRNA synthetases (ARSs), the family of enzymes that pair tRNA molecules with amino acids prior to translation on the ribosome, cause a diverse range of multi-system disorders that affect specific groups of tissues. Neurological development is impaired in most ARS-associated disorders. In addition to central nervous system defects, diseases caused by recessive mutations in cytosolic ARSs commonly affect the liver and lungs. Patients with biallelic mutations in mitochondrial ARSs often present with encephalopathies, with variable involvement of peripheral systems. Many of these disorders cause severe disability, and as understanding of their pathogenesis is currently limited, there are no effective treatments available. To address this, accurate in vivo models for most of the recessive ARS diseases are urgently needed. Here, we discuss approaches that have been taken to model recessive ARS diseases in vivo, highlighting some of the challenges that have arisen in this process, as well as key results obtained from these models. Further development and refinement of animal models is essential to facilitate a better understanding of the pathophysiology underlying recessive ARS diseases, and ultimately to enable development and testing of effective therapies.

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VARS2 Depletion Leads to Activation of the Integrated Stress Response and Disruptions in Mitochondrial Fatty Acid Oxidation

Cited by 7 publications

References 38 publications

IBAS: Interaction-bridged association studies discovering novel genes underlying complex traits

IBAS: Interaction-bridged association studies discovering novel genes underlying complex traits

Disease models of mitochondrial aminoacyl‐tRNA synthetase defects

Recessive aminoacyl-tRNA synthetase disorders: lessons learned from in vivo disease models

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