Peripheral neuropathy and cognitive impairment associated with a novel monoallelic HARS variant.pdf (7.71 MB)
Peripheral neuropathy and cognitive impairment associated with a novel monoallelic HARS variant.
journal contribution
posted on 2019-07-03, 09:05 authored by B Royer-Bertrand, P Tsouni, P Mullen, B Campos Xavier, L Mittaz Crettol, AJ Lobrinus, J Ghika, MR Baumgartner, C Rivolta, A Superti-Furga, T Kuntzer, C Francklyn, C TranBackground: A 49-year-old male presented with late-onset demyelinating peripheral neuropathy, cerebellar atrophy, and cognitive deficit. Nerve biopsy revealed intra-axonal inclusions suggestive of polyglucosan bodies, raising the suspicion of adult polyglucosan bodies disease (OMIM 263570). Methods and Results: While known genes associated with polyglucosan bodies storage were negative, whole-exome sequencing identified an unreported monoallelic variant, c.397G>T (p.Val133Phe), in the histidyl-tRNA synthetase (HARS) gene. While we did not identify mutations in genes known to be associated with polygucosan body disease, whole-exome sequencing revealed an unreported monoallelic variant, c.397G>T in the histidyl-tRNA synthetase (HARS) gene, encoding a substitution (Val133Phe) in the catalytic domain. Expression of this variant in patient cells resulted in reduced aminoacylation activity in extracts obtained from dermal fibroblasts, without compromising overall protein synthesis. Interpretation: Genetic variants in the genes coding for the different aminoacyl-tRNA synthases are associated with various clinical conditions. To date, a number of HARS variant have been associated with peripheral neuropathy, but not cognitive deficits. Further studies are needed to explore why HARS mutations confer a neuronal-specific phenotype.
Funding
Funding Information: NIGMS. Grant Number: 5R01GM054899-20
History
Citation
Annals of Clinical and Translational Neurology, 2019, 6 (6), pp. 1072-1080Author affiliation
/Organisation/COLLEGE OF LIFE SCIENCES/Biological Sciences/Genetics and Genome BiologyVersion
- VoR (Version of Record)