Peripheral neuropathy and cognitive impairment associated with a novel monoallelic HARS variant.pdf (7.71 MB)
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Peripheral neuropathy and cognitive impairment associated with a novel monoallelic HARS variant.

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journal contribution
posted on 03.07.2019, 09:05 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 Tran
Background: 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. 1072-1080

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/Biological Sciences/Genetics and Genome Biology

Version

VoR (Version of Record)

Published in

Annals of Clinical and Translational Neurology

Publisher

Wiley for American Neurological Association

issn

2328-9503

Acceptance date

05/04/2019

Copyright date

2019

Available date

03/07/2019

Publisher version

https://onlinelibrary.wiley.com/doi/full/10.1002/acn3.791

Notes

Additional supporting information may be found online in the Supporting Information section at the end of the article. Table S1. Number of variants at the different filtering steps.

Language

en

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