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Mutations in the mitochondrial tryptophanyl‐tRNA synthetase cause growth retardation and progressive leukoencephalopathy

2019; Wiley; Volume: 7; Issue: 6 Linguagem: Inglês

10.1002/mgg3.654

2324-9269

Camilla Maffezzini, Isabelle Laine, Cristina Dallabona, Paula Clemente, Javier Calvo‐Garrido, Rolf Wibom, K Naess, Michela Barbaro, Anna Falk, Claudia Donnini, Christoph Freyer, Anna Wredenberg, Anna Wedell,

RNA modifications and cancer

Abstract Background Mutations 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. Methods Whole 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. Results Biochemical 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. Conclusions Our 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.