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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)
Verlagsversion DOI PMC
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Creative Commons Lizenzvertrag
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter 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
Sprache englisch
Veröffentlichungsjahr 2014
HGF-Berichtsjahr 2014
ISSN (print) / ISBN 1059-7794
e-ISSN 1098-1004
Zeitschrift Human Mutation
Quellenangaben Band: 35, Heft: 8, Seiten: 983-989 Artikelnummer: , Supplement: ,
Verlag Wiley
Verlagsort Hoboken
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Human Genetics (IHG)
POF Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-500700-001
PubMed ID 24827421
DOI 10.1002/humu.22590
WOS ID WOS:000339431600012
Scopus ID 84904406653
Erfassungsdatum 2014-06-04
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