VARS2 and TARS2 mutations in patients with mitochondrial encephalomyopathies.

TitleVARS2 and TARS2 mutations in patients with mitochondrial encephalomyopathies.
Publication TypeJournal Article
Year of Publication2014
AuthorsDiodato, D, Melchionda, L, Haack, TB, Dallabona, C, Baruffini, E, Donnini, C, Granata, T, Ragona, F, Balestri, P, Margollicci, M, Lamantea, E, Nasca, A, Powell, CA, Minczuk, MA, Strom, TM, Meitinger, T, Prokisch, H, Lamperti, C, Zeviani, M, Ghezzi, D
JournalHum Mutat
Volume35
Issue8
Pagination983-9
Date Published2014 Aug
ISSN1098-1004
KeywordsCell Line, Child, DNA, Mitochondrial, Electron Transport Complex I, Fibroblasts, Heterozygote, HLA Antigens, Homozygote, Humans, Infant, Isoenzymes, Male, Mitochondria, Mitochondrial Encephalomyopathies, Mutation, Polymorphism, Genetic, RNA, Messenger, RNA, Transfer, Thr, RNA, Transfer, Val, Saccharomyces cerevisiae, Threonine-tRNA Ligase, Valine-tRNA Ligase
Abstract

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 Single Nucleotide Polymorphism (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.

DOI10.1002/humu.22590
Alternate JournalHum. Mutat.
Citation Key10.1002/humu.22590
PubMed ID24827421
PubMed Central IDPMC4140549
Grant ListGGP11011 / / Telethon / Italy
MC_U105697135 / / Medical Research Council / United Kingdom
MC_UP_1002/1 / / Medical Research Council / United Kingdom