Mutations in the mitochondrial tryptophanyl-tRNA synthetase cause growth retardation and progressive leukoencephalopathy
(2019) In Molecular Genetics & Genomic Medicine 7(6).- 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... (More)
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.
(Less)
- author
- publishing date
- 2019-06
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Adolescent, Adult, Amino Acid Sequence, Amino Acyl-tRNA Synthetases/genetics, Aminoacylation, Animals, Child, Disease Models, Animal, Drosophila melanogaster, Growth Disorders/genetics, Humans, Leukoencephalopathies/genetics, Mitochondria/genetics, Mitochondrial Diseases/genetics, Mutation, Pedigree, Tryptophan-tRNA Ligase/genetics, Whole Exome Sequencing
- in
- Molecular Genetics & Genomic Medicine
- volume
- 7
- issue
- 6
- article number
- e654
- pages
- 13 pages
- publisher
- John Wiley & Sons Inc.
- external identifiers
-
- scopus:85067293084
- pmid:30920170
- ISSN
- 2324-9269
- DOI
- 10.1002/mgg3.654
- language
- English
- LU publication?
- no
- id
- 7e92c3c4-5880-4a2a-9c65-6323d29912ec
- date added to LUP
- 2021-08-09 15:48:19
- date last changed
- 2024-06-16 16:34:21
@article{7e92c3c4-5880-4a2a-9c65-6323d29912ec,
abstract = {{<p>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.</p><p>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.</p><p>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.</p><p>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.</p>}},
author = {{Maffezzini, Camilla and Laine, Isabelle and Dallabona, Cristina and Clemente, Paula and Calvo-Garrido, Javier and Wibom, Rolf and Naess, Karin and Barbaro, Michela and Falk, Anna and Donnini, Claudia and Freyer, Christoph and Wredenberg, Anna and Wedell, Anna}},
issn = {{2324-9269}},
keywords = {{Adolescent; Adult; Amino Acid Sequence; Amino Acyl-tRNA Synthetases/genetics; Aminoacylation; Animals; Child; Disease Models, Animal; Drosophila melanogaster; Growth Disorders/genetics; Humans; Leukoencephalopathies/genetics; Mitochondria/genetics; Mitochondrial Diseases/genetics; Mutation; Pedigree; Tryptophan-tRNA Ligase/genetics; Whole Exome Sequencing}},
language = {{eng}},
number = {{6}},
publisher = {{John Wiley & Sons Inc.}},
series = {{Molecular Genetics & Genomic Medicine}},
title = {{Mutations in the mitochondrial tryptophanyl-tRNA synthetase cause growth retardation and progressive leukoencephalopathy}},
url = {{https://lup.lub.lu.se/search/files/101035619/Mutations_in_the_mitochondrial_tryptophanyl.pdf}},
doi = {{10.1002/mgg3.654}},
volume = {{7}},
year = {{2019}},
}