Bi-allelic mutations in HARS1 severely impair histidyl-tRNA synthetase expression and enzymatic activity causing a novel multisystem ataxic syndrome: Human Mutation

D. Galatolo, M.E. Kuo, P. Mullen, R. Meyer-Schuman, S. Doccini, R. Battini, M. Lieto, A. Tessa, A. Filla, C. Francklyn, A. Antonellis, F.M. Santorelli

Research output: Contribution to journalArticlepeer-review

Abstract

Mutations in histidyl-tRNA synthetase (HARS1), an enzyme that charges transfer RNA with the amino acid histidine in the cytoplasm, have only been associated to date with autosomal recessive Usher syndrome type III and autosomal dominant Charcot–Marie–Tooth disease type 2W. Using massive parallel sequencing, we identified bi-allelic HARS1 variants in a child (c.616G>T, p.Asp206Tyr and c.730delG, p.Val244Cysfs*6) and in two sisters (c.1393A>C, p.Ile465Leu and c.910_912dupTTG, p.Leu305dup), all characterized by a multisystem ataxic syndrome. All mutations are rare, segregate with the disease, and are predicted to have a significant effect on protein function. Functional studies helped to substantiate their disease-related roles. Indeed, yeast complementation assays showing that one out of two mutations in each patient is loss-of-function, and the reduction of messenger RNA and protein levels and enzymatic activity in patient's skin-derived fibroblasts, together support the pathogenicity of the identified HARS1 variants in the patient phenotypes. Thus, our efforts expand the allelic and clinical spectrum of HARS1-related disease. © 2020 Wiley Periodicals, Inc.
Original languageEnglish
Pages (from-to)1232-1237
Number of pages6
JournalHum. Mutat.
Volume41
Issue number7
DOIs
Publication statusPublished - 2020

Keywords

  • aminoacylation assay
  • autosomal recessive
  • exome sequencing
  • hereditary ataxia
  • multigene resequencing panel
  • yeast complementation assay
  • aspartic acid
  • cysteine
  • histidine
  • histidine transfer RNA ligase
  • isoleucine
  • leucine
  • messenger RNA
  • transfer RNA
  • tyrosine
  • valine
  • adult
  • allele
  • Article
  • autosomal dominant inheritance
  • case report
  • child
  • clinical article
  • controlled study
  • enzyme activity
  • female
  • fibroblast
  • gene
  • gene mutation
  • genetic complementation
  • genetic variability
  • hars1 gene
  • hereditary motor sensory neuropathy
  • human
  • human cell
  • loss of function mutation
  • male
  • massively parallel signature sequencing
  • nuclear magnetic resonance imaging
  • pathogenicity
  • phenotype
  • priority journal
  • protein expression
  • school child
  • sister
  • skin fibroblast
  • Usher syndrome

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