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Diodato, D.* ; Melchionda, L.* ; Haack, T.B. ; Dallabona, C.* ; Baruffini, E.* ; Donnini, C.* ; Granata, T.* ; Ragona, F.* ; Balestri, P.* ; Margollicci, M.* ; Lamantea, E.* ; Nasca, A.* ; Powell, C.A.* ; Minczuk, M.* ; Strom, T.M. ; Meitinger, T. ; Prokisch, H. ; Lamperti, C.* ; Zeviani, M.* ; Ghezzi, D.*

VARS2 and TARS2 mutations in patients with mitochondrial encephalomyopathies.

Hum. Mutat. 35, 983-989 (2014)
Publ. Version/Full Text DOI PMC
Creative Commons Lizenzvertrag
Open Access Green as soon as Postprint is submitted to ZB.
By way of whole-exome sequencing we identified: a homozygous missense mutation in VARS2, in one subject with microcephaly and epilepsy associated with isolated deficiency of the mitochondrial respiratory chain (MRC) complex I; and compound heterozygous mutations in TARS2, in two siblings presenting with axial hypotonia and severe psychomotor delay associated with multiple MRC defects. The nucleotide variants segregated within the families, were absent in SNP databases, and are predicted to be deleterious. The amount of VARS2 and TARS2 proteins and valyl-tRNA and threonyl-tRNA levels were decreased in samples of afflicted patients according to the genetic defect. Expression of the corresponding wild-type transcripts in immortalized mutant fibroblasts rescued the biochemical impairment of mitochondrial respiration and yeast modeling of the VARS2 mutation confirmed its pathogenic role. Taken together, these data demonstrate the role of the identified mutations for these mitochondriopathies. Our study reports the first mutations in the VARS2 and TARS2 genes, which encode two mitochondrial aminoacyl-tRNA synthetases, as causes of clinically distinct, early-onset mitochondrial encephalopathies.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Oxphos Defect ; Tars2 ; Vars2 ; Aminoacyl Trna Syntethases ; Encephalomyopathy ; Mitochondrial Disease; Transfer-rna Synthetases; Complex-i Deficiency; Lactic-acidosis; Brain-stem; Cells; Leukoencephalopathy; Cardiomyopathy; Involvement; Disease; Gene
ISSN (print) / ISBN 1059-7794
e-ISSN 1098-1004
Journal Human Mutation
Quellenangaben Volume: 35, Issue: 8, Pages: 983-989 Article Number: , Supplement: ,
Publisher Wiley
Publishing Place Hoboken
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)