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Mol Genet Genomic Med. 2019 Jun;7(6):e654. doi: 10.1002/mgg3.654. Epub 2019 Mar 28.

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

Author information

1
Max Planck Institute Biology of Ageing - Karolinska Institutet Laboratory, Stockholm, Sweden.
2
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
3
Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy.
4
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
5
Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.
6
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.

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.

KEYWORDS:

WARS2; aminoacylation; mitochondria; mitochondrial tryptophanyl-tRNA synthetase

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