Abstract
Background
Alanyl-tRNA synthetase 1 (AARS1) gene encodes a ubiquitously expressed class II enzyme that catalyzes the attachment of alanine to the cognate tRNA. AARS1 mutations are frequently responsible for autosomal dominant Charcot-Marie-Tooth disease type 2N (CMT2N).
Objective
To identify pathogenic mutation in the Korean patients with CMT and distal hereditary motor neuronopathy (dHMN).
Methods
We screened AARS1 mutations in 373 unrelated CMT families including 318 axonal CMT, 36 dHMN, and 19 intermediate CMT (Int-CMT) who were negative for 17p12 (PMP22) duplication or deletion using whole exome sequencing and targeted sequencing of CMT-related genes.
Results
This study identified an early onset Int-CMT family harboring an AARS1 p.Arg329His mutation which was previously reported as pathogenic in French and Australian families. The mutation was located in the highly conserved tRNA binding domain and several in silico analyses suggested pathogenic prediction of the mutations. The patients harboring p.Arg329His showed clinically similar phenotypes of the early onset and electrophysiological intermediate type as those in Australian patients with same mutation. We also found a novel c.2564A>G (p.Gln855Arg) in a CMT2 patient, but its’ pathogenic role was uncertain (variant of uncertain significance).
Conclusion
This study suggests that the frequency of the AARS1 mutations appears to be quite low in Korean CMT. This is the first report of the AARS1 mutation in Korean CMT patients and will be helpful for the exact molecular diagnosis and treatment of Int-CMT patients.
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Acknowledgements
We thank the patients and their families for consenting to participation and sample donation for this study. This work was supported by Grants from the National Research Foundation (2016R1A5A2007009, 2018R1A4A1024506 and 2019R1A2C1087547) and the Korean Health Technology R&D Project, Ministry of Health and Welfare (HI14C3484 and HI16C0426), Republic of Korea.
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BOC and KWC were major contributors to the experimental design. AJL and DEN performed molecular genetic works. BOC and SHN collected patient samples. BOC and KWC were involved in writing the manuscript and data analysis and interpretation. All authors read and approved the final manuscript.
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AJL, DEN, YJC, SHN, BOC, and KWC declare that they have no conflict of interest.
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All participants provided written informed consent, and the study protocol was approved by the Institutional Review Boards for Sungkyunkwan University School of Medicine, Samsung Medical Center (SMC, 2014-08-057-002), and Kongju National University (KNU-IRB-2018-06).
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Lee, A.J., Nam, D.E., Choi, Y.J. et al. Alanyl-tRNA synthetase 1 (AARS1) gene mutation in a family with intermediate Charcot-Marie-Tooth neuropathy. Genes Genom 42, 663–672 (2020). https://doi.org/10.1007/s13258-020-00933-9
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DOI: https://doi.org/10.1007/s13258-020-00933-9