VARS2 and TARS2 mutations in patients with mitochondrial encephalomyopathies.
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.
Unit of Molecular Neurogenetics, Fondazione IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Istituto Neurologico "Carlo Besta", Milan, Italy.
Daria
D
Diodato
Laura
L
Melchionda
Tobias B
TB
Haack
Cristina
C
Dallabona
Enrico
E
Baruffini
Claudia
C
Donnini
Tiziana
T
Granata
Francesca
F
Ragona
Paolo
P
Balestri
Maria
M
Margollicci
Eleonora
E
Lamantea
Alessia
A
Nasca
Christopher A
CA
Powell
Michal
M
Minczuk
Tim M
TM
Strom
Thomas
T
Meitinger
Holger
H
Prokisch
Costanza
C
Lamperti
Massimo
M
Zeviani
Daniele
D
Ghezzi
D002460:Cell Line; D002648:Child; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006680:HLA Antigens / Q000235:genetics* / Q000378:metabolism; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D017237:Mitochondrial Encephalomyopathies / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012363:RNA, Transfer, Thr / Q000235:genetics / Q000378:metabolism; D012366:RNA, Transfer, Val / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D013914:Threonine-tRNA Ligase / Q000235:genetics* / Q000378:metabolism; D014637:Valine-tRNA Ligase / Q000235:genetics* / Q000378:metabolism
D004272:DNA, Mitochondrial; D006680:HLA Antigens; D007527:Isoenzymes; D012333:RNA, Messenger; D012363:RNA, Transfer, Thr; D012366:RNA, Transfer, Val; C070977:VARS2 protein, human; D013914:Threonine-tRNA Ligase; D014637:Valine-tRNA Ligase; D042967:Electron Transport Complex I
OXPHOS defect; TARS2; VARS2; aminoacyl tRNA syntethases; encephalomyopathy; mitochondrial disease