Dominant NARS1 mutations causing axonal Charcot-Marie-Tooth disease expand NARS1-associated diseases
Document Type
Article
Publication Date
1-1-2024
Original Citation
Beijer D,
Marte S,
Li J,
De Ridder W,
Chen J,
Tadenev A,
Miers K,
Deconinck T,
Macdonell R,
Marques W,
De Jonghe P,
Pratt S,
Meyer-Schuman R,
Züchner S,
Antonellis A,
Burgess RW,
Baets J.
Dominant NARS1 mutations causing axonal Charcot-Marie-Tooth disease expand NARS1-associated diseases Brain Commun. 2024;6(2):fcae070
Keywords
JMG, SS1
JAX Source
Brain Commun. 2024;6(2):fcae070
ISSN
2632-1297
PMID
38495304
DOI
https://doi.org/10.1093/braincomms/fcae070
Grant
R.W.B is supported by grants from the National Institutes of Health (NIH) (R24NS098523 and R37NS054154).
Abstract
Pathogenic variants in six aminoacyl-tRNA synthetase (ARS) genes are implicated in neurological disorders, most notably inherited per- ipheral neuropathies. ARSs are enzymes that charge tRNA molecules with cognate amino acids. Pathogenic variants in asparaginyl- tRNA synthetase (NARS1) cause a neurological phenotype combining developmental delay, ataxia and demyelinating peripheral neur- opathy. NARS1 has not yet been linked to axonal Charcot–Marie–Tooth disease. Exome sequencing of patients with inherited periph- eral neuropathies revealed three previously unreported heterozygous NARS1 variants in three families. Clinical and electrophysiological details were assessed. We further characterized all three variants in a yeast complementation model and used a knock-in mouse model to study variant p.Ser461Phe. All three variants (p.Met236del, p.Cys342Tyr and p.Ser461Phe) co-segregate with the sensorimotor axonal neuropathy phenotype. Yeast complementation assays show that none of the three NARS1 variants support wild-type yeast growth when tested in isolation (i.e. in the absence of a wild-type copy of NARS1), consistent with a loss-of-function effect. Similarly, the homo- zygous knock-in mouse model (p.Ser461Phe/Ser472Phe in mouse) also demonstrated loss-of-function characteristics. We present three previously unreported NARS1 variants segregating with a sensorimotor neuropathy phenotype in three families. Functional studies in yeast and mouse support variant pathogenicity. Thus, NARS1 is the seventh ARS implicated in dominant axonal Charcot–Marie–Tooth disease, further stressing that all dimeric ARSs should be evaluated for Charcot–Marie–Tooth disease.
Comments
This Open Access article contains public sector information licensed under the Open Government Licence v3.0 (http://www.nationalarchives.gov.uk/doc/open-government-licence/ version/3/)