Deficiency of WARS2, encoding mitochondrial tryptophanyl tRNA synthetase, causes severe infantile onset leukoencephalopathy

Benjamin E. Theisen, Anastasia Rumyantseva, Julie S. Cohen, Wendy A. Alcaraz, Deepali N. Shinde, Sha Tang, Siddarth Srivastava, Jonathan Pevsner, Aleksandra Trifunovic, Ali Fatemi

Research output: Contribution to journalArticle

Abstract

Pathogenic variants in the mitochondrial aminoacyl tRNA synthetases lead to deficiencies in mitochondrial protein synthesis and are associated with a broad range of clinical presentations usually with early onset and inherited in an autosomal recessive manner. Of the 19 mitochondrial aminoacyl tRNA synthetases, WARS2, encoding mitochondrial tryptophanyl tRNA synthetase, was as of late the only one that had not been associated with disease in humans. A case of a family with pathogenic variants in WARS2 that caused mainly intellectual disability, speech impairment, aggressiveness, and athetosis was recently reported. Here we substantially extend and consolidate the symptomatology of WARS2 by presenting a patient with severe infantile-onset leukoencephalopathy, profound intellectual disability, spastic quadriplegia, epilepsy, microcephaly, short stature, failure to thrive, cerebral atrophy, and periventricular white matter abnormalities. He was found by whole-exome sequencing to have compound heterozygous variants in WARS2, c.938A>T (p.K313M) and c.298_300delCTT (p.L100del). De novo synthesis of proteins inside mitochondria was reduced in the patient's fibroblasts, leading to significantly lower steady-state levels of respiratory chain subunits compared to control and resulting in lower oxygen consumption rates.

Original languageEnglish (US)
JournalAmerican Journal of Medical Genetics, Part A
DOIs
StateAccepted/In press - 2017

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Tryptophan-tRNA Ligase
Leukoencephalopathies
Amino Acyl-tRNA Synthetases
Intellectual Disability
Athetosis
Exome
Failure to Thrive
Microcephaly
Quadriplegia
Mitochondrial Proteins
Electron Transport
Oxygen Consumption
Atrophy
Epilepsy
Mitochondria
Fibroblasts
Proteins
White Matter

Keywords

  • Aminoacyl tRNA synthetase
  • Aminoacylation
  • Brain
  • Intellectual disability
  • Leukoencephalopathy
  • Mitochondria

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Deficiency of WARS2, encoding mitochondrial tryptophanyl tRNA synthetase, causes severe infantile onset leukoencephalopathy. / Theisen, Benjamin E.; Rumyantseva, Anastasia; Cohen, Julie S.; Alcaraz, Wendy A.; Shinde, Deepali N.; Tang, Sha; Srivastava, Siddarth; Pevsner, Jonathan; Trifunovic, Aleksandra; Fatemi, Ali.

In: American Journal of Medical Genetics, Part A, 2017.

Research output: Contribution to journalArticle

Theisen, Benjamin E.; Rumyantseva, Anastasia; Cohen, Julie S.; Alcaraz, Wendy A.; Shinde, Deepali N.; Tang, Sha; Srivastava, Siddarth; Pevsner, Jonathan; Trifunovic, Aleksandra; Fatemi, Ali / Deficiency of WARS2, encoding mitochondrial tryptophanyl tRNA synthetase, causes severe infantile onset leukoencephalopathy.

In: American Journal of Medical Genetics, Part A, 2017.

Research output: Contribution to journalArticle

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