期刊
MOLECULAR GENETICS & GENOMIC MEDICINE
卷 7, 期 6, 页码 -出版社
WILEY
DOI: 10.1002/mgg3.654
关键词
aminoacylation; mitochondria; mitochondrial tryptophanyl-tRNA synthetase; WARS2
资金
- Vetenskapsradet [2016-01082, 2016-02179, VR521-201-2571]
- Hjarnfonden [FO2015-0146]
- Knut och Alice Wallenbergs Stiftelse [2013.0026, 2014.0293]
- Stockholms Lans Landsting [20140053, K0176-2012]
- Stiftelsen for Strategisk Forskning [ICA 12-0017]
- Fondazione Telethon [GGP15041]
- Ragnar Soderbergs stiftelse [M77/13]
- Swedish Research Council [2016-01082, 2016-02179, VR521-201-2571]
- Stockholm County Council [20140053, K0176-2012]
- Swedish Foundation for Strategic Research [0026, 0293]
- Brain Foundation [FO2015-0146, GGP15041, M77, 13]
- Telethon Foundation
- Karolinska Institutet
- Swedish Research Council [2016-01082, 2016-02179] Funding Source: Swedish Research Council
BackgroundMutations in mitochondrial aminoacyl tRNA synthetases form a subgroup of mitochondrial disorders often only perturbing brain function by affecting mitochondrial translation. Here we report two siblings with mitochondrial disease, due to compound heterozygous mutations in the mitochondrial tryptophanyl-tRNA synthetase (WARS2) gene, presenting with severe neurological symptoms but normal mitochondrial function in skeletal muscle biopsies and cultured skin fibroblasts. MethodsWhole exome sequencing on genomic DNA samples from both subjects and their parents identified two compound heterozygous variants c.833T>G (p.Val278Gly) and c.938A>T (p.Lys313Met) in the WARS2 gene as potential disease-causing variants. We generated patient-derived neuroepithelial stem cells and modeled the disease in yeast and Drosophila melanogaster to confirm pathogenicity. ResultsBiochemical analysis of patient-derived neuroepithelial stem cells revealed a mild combined complex I and IV defect, while modeling the disease in yeast demonstrated that the reported aminoacylation defect severely affects respiration and viability. Furthermore, silencing of wild type WARS2 in Drosophila melanogaster showed that a partial defect in aminoacylation is enough to cause lethality. ConclusionsOur results establish the identified WARS2 variants as disease-causing and highlight the benefit of including human neuronal models, when investigating mutations specifically affecting the nervous system.
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