PMID:22448145

Citation	Bayat, V, Thiffault, I, Jaiswal, M, Tétreault, M, Donti, T, Sasarman, F, Bernard, G, Demers-Lamarche, J, Dicaire, MJ, Mathieu, J, Vanasse, M, Bouchard, JP, Rioux, MF, Lourenco, CM, Li, Z, Haueter, C, Shoubridge, EA, Graham, BH, Brais, B and Bellen, HJ (2012) Mutations in the mitochondrial methionyl-tRNA synthetase cause a neurodegenerative phenotype in flies and a recessive ataxia (ARSAL) in humans. PLoS Biol. 10:e1001288
Abstract	An increasing number of genes required for mitochondrial biogenesis, dynamics, or function have been found to be mutated in metabolic disorders and neurological diseases such as Leigh Syndrome. In a forward genetic screen to identify genes required for neuronal function and survival in Drosophila photoreceptor neurons, we have identified mutations in the mitochondrial methionyl-tRNA synthetase, Aats-met, the homologue of human MARS2. The fly mutants exhibit age-dependent degeneration of photoreceptors, shortened lifespan, and reduced cell proliferation in epithelial tissues. We further observed that these mutants display defects in oxidative phosphorylation, increased Reactive Oxygen Species (ROS), and an upregulated mitochondrial Unfolded Protein Response. With the aid of this knowledge, we identified MARS2 to be mutated in Autosomal Recessive Spastic Ataxia with Leukoencephalopathy (ARSAL) patients. We uncovered complex rearrangements in the MARS2 gene in all ARSAL patients. Analysis of patient cells revealed decreased levels of MARS2 protein and a reduced rate of mitochondrial protein synthesis. Patient cells also exhibited reduced Complex I activity, increased ROS, and a slower cell proliferation rate, similar to Drosophila Aats-met mutants.
Links	PubMed PMC3308940 Online version:10.1371/journal.pbio.1001288
Keywords	Adolescent; Adult; Animals; Ataxia/genetics; Ataxia/metabolism; Cell Proliferation; Child; Child, Preschool; Drosophila/enzymology; Drosophila/genetics; Drosophila/physiology; Drosophila Proteins/genetics; Drosophila Proteins/metabolism; Electron Transport; Electroretinography/methods; Female; Gene Expression Regulation, Enzymologic; HEK293 Cells; Humans; Leukoencephalopathies/genetics; Leukoencephalopathies/metabolism; Longevity; Male; Methionine-tRNA Ligase/genetics; Methionine-tRNA Ligase/metabolism; Middle Aged; Mitochondria/enzymology; Mitochondria/genetics; Mitochondrial Proteins/genetics; Mitochondrial Proteins/metabolism; Muscles/metabolism; Muscles/physiopathology; Mutation; Neurodegenerative Diseases/genetics; Neurodegenerative Diseases/metabolism; Oxidative Phosphorylation; Pedigree; Phenotype; Photoreceptor Cells/metabolism; Photoreceptor Cells/pathology; Reactive Oxygen Species/metabolism; Retina/metabolism; Retina/pathology; Unfolded Protein Response; Young Adult
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
DROME:SYMM		GO:0045494: photoreceptor cell maintenance	ECO:0000315:		P		Figure 2: Loss of Aats-met in the Eye Results in Retinal Degeneration	complete CACAO 5883
DROME:SYMM		GO:0008340: determination of adult lifespan	ECO:0000315:		P		Figure 2J, 3A, 3C: Loss of Aats-met Results in Reduced Lifespan	complete CACAO 5884
DROME:SYMM		GO:0044429: mitochondrial part	ECO:0000315:		C		Figure 3C-E: Mitochondria are clearly aberrant; they are larger than normal	complete CACAO 5885
DROME:SYMM		GO:0007629 : flight behavior	ECO:0000315:		P		Figure 2: mutants missing Aats-mets are unable to fly.	complete CACAO 5890

References

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