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Human Genetics

, Volume 137, Issue 4, pp 293–303 | Cite as

Loss of function mutations in VARS encoding cytoplasmic valyl-tRNA synthetase cause microcephaly, seizures, and progressive cerebral atrophy

  • Joshi Stephen
  • Sheela Nampoothiri
  • Aditi Banerjee
  • Nathanial J. Tolman
  • Josef Martin Penninger
  • Ullrich Elling
  • Chukwuma A. Agu
  • John D. Burke
  • Kalpana Devadathan
  • Rajesh Kannan
  • Yan Huang
  • Peter J. Steinbach
  • Susan A. Martinis
  • William A. Gahl
  • May Christine V. MalicdanEmail author
Original Investigation

Abstract

Progressive microcephaly and neurodegeneration are genetically heterogenous conditions, largely associated with genes that are essential for the survival of neurons. In this study, we interrogate the genetic etiology of two siblings from a non-consanguineous family with severe early onset of neurological manifestations. Whole exome sequencing identified novel compound heterozygous mutations in VARS that segregated with the proband: a missense (c.3192G>A; p.Met1064Ile) and a splice site mutation (c.1577-2A>G). The VARS gene encodes cytoplasmic valyl-tRNA synthetase (ValRS), an enzyme that is essential during eukaryotic translation. cDNA analysis on patient derived fibroblasts revealed that the splice site acceptor variant allele led to nonsense mediated decay, thus resulting in a null allele. Three-dimensional modeling of ValRS predicts that the missense mutation lies in a highly conserved region and could alter side chain packing, thus affecting tRNA binding or destabilizing the interface between the catalytic and tRNA binding domains. Further quantitation of the expression of VARS showed remarkably reduced levels of mRNA and protein in skin derived fibroblasts. Aminoacylation experiments on patient derived cells showed markedly reduced enzyme activity of ValRS suggesting the mutations to be loss of function. Bi-allelic mutations in cytoplasmic amino acyl tRNA synthetases are well-known for their role in neurodegenerative disorders, yet human disorders associated with VARS mutations have not yet been clinically well characterized. Our study describes the phenotype associated with recessive VARS mutations and further functional delineation of the pathogenicity of novel variants identified, which widens the clinical and genetic spectrum of patients with progressive microcephaly.

Notes

Acknowledgements

We thank patient and family for participating in this study.

Funding

This work was supported by the Intramural Research Programs of the National Human Genome Research Institute and the Center for Information Technology, National Institutes of Health, USA.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

439_2018_1882_MOESM1_ESM.docx (45 kb)
Supplementary material 1 (DOCX 45 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018 (outside the usa) 2018

Authors and Affiliations

  • Joshi Stephen
    • 1
  • Sheela Nampoothiri
    • 2
  • Aditi Banerjee
    • 3
  • Nathanial J. Tolman
    • 4
  • Josef Martin Penninger
    • 5
  • Ullrich Elling
    • 5
  • Chukwuma A. Agu
    • 5
  • John D. Burke
    • 1
  • Kalpana Devadathan
    • 6
  • Rajesh Kannan
    • 7
  • Yan Huang
    • 8
  • Peter J. Steinbach
    • 9
  • Susan A. Martinis
    • 3
  • William A. Gahl
    • 1
    • 4
    • 8
  • May Christine V. Malicdan
    • 1
    • 4
    • 8
    Email author
  1. 1.Section of Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research InstituteNational Institutes of HealthBethesdaUSA
  2. 2.Department of Pediatric GeneticsAmrita Institute of Medical Sciences and Research CenterCochinIndia
  3. 3.Department of BiochemistryUniversity of Illinois at Urbana-ChampaignUrbanaUSA
  4. 4.Office of the Clinical Director, National Human Genome Research Institute (NHGRI)National Institutes of HealthBethesdaUSA
  5. 5.Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA), Vienna Biocenter (VBC)ViennaAustria
  6. 6.Department of Pediatric NeurologyKIMS HospitalThiruvananthapuramIndia
  7. 7.Department of RadiologyAmrita Institute of Medical Sciences and Research CenterCochinIndia
  8. 8.NIH Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI) and the Common FundNational Institutes of HealthBethesdaUSA
  9. 9.Center for Molecular Modeling, Center for Information TechnologyNational Institutes of HealthBethesdaUSA

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