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

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

  • Hum Genet. 2018 Apr;137(4):293-303. doi: 10.1007/s00439-018-1882-3.
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 10 11 12
Affiliations

Affiliations

  • 1 Section of Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
  • 2 Department of Pediatric Genetics, Amrita Institute of Medical Sciences and Research Center, Cochin, Kerala, India.
  • 3 Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
  • 4 Office of the Clinical Director, National Human Genome Research Institute (NHGRI), National Institutes of Health, Bethesda, MD, USA.
  • 5 Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA), Vienna Biocenter (VBC), Dr. Bohr Gasse 3, Vienna, Austria.
  • 6 Department of Pediatric Neurology, KIMS Hospital, Thiruvananthapuram, Kerala, India.
  • 7 Department of Radiology, Amrita Institute of Medical Sciences and Research Center, Cochin, Kerala, India.
  • 8 NIH Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI) and the Common Fund, National Institutes of Health, Bethesda, MD, USA.
  • 9 Center for Molecular Modeling, Center for Information Technology, National Institutes of Health, Bethesda, MD, USA.
  • 10 Section of Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. [email protected].
  • 11 Office of the Clinical Director, National Human Genome Research Institute (NHGRI), National Institutes of Health, Bethesda, MD, USA. [email protected].
  • 12 NIH Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI) and the Common Fund, National Institutes of Health, Bethesda, MD, USA. [email protected].
PMID: 29691655 DOI: 10.1007/s00439-018-1882-3
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.

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