Reference Report

Reference
Citation	Bayat, V., Thiffault, I., Jaiswal, M., Tétreault, M., Donti, T., Sasarman, F., Bernard, G., Demers-Lamarche, J., Dicaire, M.J., Mathieu, J., Vanasse, M., Bouchard, J.P., Rioux, M.F., Lourenco, C.M., Li, Z., Haueter, C., Shoubridge, E.A., Graham, B.H., Brais, B., Bellen, H.J. (2012). Mutations in the Mitochondrial Methionyl-tRNA Synthetase Cause a Neurodegenerative Phenotype in Flies and a Recessive Ataxia (ARSAL) in Humans. PLoS Biol. 10(3): e1001288. (Export to RIS)
FlyBase ID	FBrf0217845
Publication Type	Research paper
PubMed ID	22448145
PubMed 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.
DOI	10.1371/journal.pbio.1001288
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Language of Publication	English
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Publication Type	Journal
Abbreviation	PLoS Biol.
Title	PLoS Biology
Publication Year	2003-
ISBN/ISSN	1545-7885 1544-9173
Data from Reference
Aberrations (1)
	Df(3R)Exel7321
Alleles (11)
	Aats-met^c00449 Aats-met^FB Aats-met^HV Aats-met^Scer\UAS.cBa Avic\GFP^{S65T.Scer\UAS.T:Ivir\HA1,T:Hsap\mito} BacA\p35^Scer\UAS.cHa Hsap\MARS2^Scer\UAS.cBa Hsap\MARS2^{Scer\UAS.T:Zzzz\FLAG} Scer\GAL4^Act5C.PU Scer\GAL4^D42 Scer\GAL4^tub.PU
Constructs (7)
	P{Act5C-GAL4.U} P{tub-GAL4.U} P{UAS-mito-HA-GFP.AP} P{UAS-p35.H} PBac{UAS-Aats-met.B} PBac{UAS-HMARS2.B} PBac{UAS-HMARS2.FLAG}
Genes (10)
	Aats-met Acon Avic\GFP BacA\p35 dlg1 Hsap\MARS2 Hsc70-3 Hsp60 Scer\GAL4 T:Zzzz\FLAG
Insertions (5)
	P{GawB}D42 PBac{UAS-Aats-met.B}VK00037 PBac{UAS-HMARS2.B}VK00037 PBac{UAS-HMARS2.FLAG}VK00037 PBac{y⁺-attP-3B}VK00037
Natural transposons (1)
	Tni\piggyBac