Biallelic mutations in mitochondrial tryptophanyl-tRNA synthetase cause Levodopa-responsive infantile-onset Parkinsonism

E. A. Burke, S. J. Frucht, K. Thompson, L. A. Wolfe, T. Yokoyama, M. Bertoni, Y. Huang, M. Sincan, D. R. Adams, R. W. Taylor, W. A. Gahl, C. Toro, M. C.V. Malicdan

Research output: Contribution to journalArticle

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Abstract

Mitochondrial aminoacyl-tRNA synthetases (mtARSs) are essential, ubiquitously expressed enzymes that covalently attach amino acids to their corresponding tRNA molecules during translation of mitochondrial genes. Deleterious variants in the mtARS genes cause a diverse array of phenotypes, many of which involve the nervous system. Moreover, distinct mutations in mtARSs often cause different clinical manifestations. Recently, the gene encoding mitochondrial tryptophanyl tRNA synthetase (WARS2) was reported to cause 2 different neurological phenotypes, a form of autosomal recessive intellectual disability and a syndrome of severe infantile-onset leukoencephalopathy. Here, we report the case of a 17-year-old boy with compound heterozygous mutations in WARS2 (p.Trp13Gly, p.Ser228Trp) who presented with infantile-onset, Levodopa-responsive Parkinsonism at the age of 2 years. Analysis of patient-derived dermal fibroblasts revealed decreased steady-state WARS2 protein and normal OXPHOS content. Muscle mitochondrial studies suggested mitochondrial proliferation without obvious respiratory chain deficiencies at the age of 9 years. This case expands the phenotypic spectrum of WARS2 deficiency and emphasizes the importance of mitochondrial protein synthesis in the pathogenesis of Parkinsonism.

Original languageEnglish (US)
Pages (from-to)712-718
Number of pages7
JournalClinical Genetics
Volume93
Issue number3
DOIs
StatePublished - Mar 2018

Fingerprint

Tryptophan-tRNA Ligase
Amino Acyl-tRNA Synthetases
Mitochondrial Genes
Parkinsonian Disorders
Levodopa
Phenotype
Leukoencephalopathies
Mutation
Mitochondrial Proteins
Electron Transport
Transfer RNA
Intellectual Disability
Nervous System
Fibroblasts
Amino Acids
Muscles
Skin
Enzymes
Genes
Proteins

Keywords

  • Parkinsonism
  • medical genetics
  • precision medicine
  • tRNA synthetase

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Burke, E. A., Frucht, S. J., Thompson, K., Wolfe, L. A., Yokoyama, T., Bertoni, M., ... Malicdan, M. C. V. (2018). Biallelic mutations in mitochondrial tryptophanyl-tRNA synthetase cause Levodopa-responsive infantile-onset Parkinsonism. Clinical Genetics, 93(3), 712-718. https://doi.org/10.1111/cge.13172

Biallelic mutations in mitochondrial tryptophanyl-tRNA synthetase cause Levodopa-responsive infantile-onset Parkinsonism. / Burke, E. A.; Frucht, S. J.; Thompson, K.; Wolfe, L. A.; Yokoyama, T.; Bertoni, M.; Huang, Y.; Sincan, M.; Adams, D. R.; Taylor, R. W.; Gahl, W. A.; Toro, C.; Malicdan, M. C.V.

In: Clinical Genetics, Vol. 93, No. 3, 03.2018, p. 712-718.

Research output: Contribution to journalArticle

Burke, EA, Frucht, SJ, Thompson, K, Wolfe, LA, Yokoyama, T, Bertoni, M, Huang, Y, Sincan, M, Adams, DR, Taylor, RW, Gahl, WA, Toro, C & Malicdan, MCV 2018, 'Biallelic mutations in mitochondrial tryptophanyl-tRNA synthetase cause Levodopa-responsive infantile-onset Parkinsonism', Clinical Genetics, vol. 93, no. 3, pp. 712-718. https://doi.org/10.1111/cge.13172
Burke, E. A. ; Frucht, S. J. ; Thompson, K. ; Wolfe, L. A. ; Yokoyama, T. ; Bertoni, M. ; Huang, Y. ; Sincan, M. ; Adams, D. R. ; Taylor, R. W. ; Gahl, W. A. ; Toro, C. ; Malicdan, M. C.V. / Biallelic mutations in mitochondrial tryptophanyl-tRNA synthetase cause Levodopa-responsive infantile-onset Parkinsonism. In: Clinical Genetics. 2018 ; Vol. 93, No. 3. pp. 712-718.
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