Document Type
Article
Publication Date
4-1-2019
Abstract
Objective: To expand the clinical spectrum of lysyl-tRNA synthetase (KARS) gene–related diseases, which so far includes Charcot-Marie-Tooth disease, congenital visual impairment and microcephaly, and nonsyndromic hearing impairment.
Methods: Whole-exome sequencing was performed on index patients from 4 unrelated families with leukoencephalopathy. Candidate pathogenic variants and their cosegregation were confirmed by Sanger sequencing. Effects of mutations on KARS protein function were examined by aminoacylation assays and yeast complementation assays.
Results: Common clinical features of the patients in this study included impaired cognitive ability, seizure, hypotonia, ataxia, and abnormal brain imaging, suggesting that the CNS involvement is the main clinical presentation. Six previously unreported and 1 known KARS mutations were identified and cosegregated in these families. Two patients are compound heterozygous for missense mutations, 1 patient is homozygous for a missense mutation, and 1 patient harbored an insertion mutation and a missense mutation. Functional and structural analyses revealed that these mutations impair aminoacylation activity of lysyl-tRNA synthetase, indicating that de- fective KARS function is responsible for the phenotypes in these individuals.
Conclusions: Our results demonstrate that patients with loss-of-function KARS mutations can manifest CNS disorders, thus broadening the phenotypic spectrum associated with KARS-related disease.
Recommended Citation
Sun, Chong; Song, Jie; Jiang, Yanjun; Zhao, Chongbo; Lu, Jiahong; Li, Yuxin; Wang, Yin; Gao, Mingshi; Xi, Jianying; Luo, Sushan; Li, Meixia; Donaldson, Kevin; Oprescu, Stephanie N.; Slavin, Thomas P.; Lee, Sansan; Magoulas, Pilar L.; Lewis, Andrea M.; Emrick, Lisa; Lalani, Seema R.; Niu, Zhiyv; Landsverk, Megan L.; Walkiewicz, Magdalena; Person, Richard E.; Mei, Hui; Rosenfeld, Jill A.; Yang, Yaping; Antonellis, Anthony; Hou, Ya-Ming; Lin, Jie; and Zhang, Victor W., "Loss-of-function mutations in Lysyl-tRNA synthetase cause various leukoencephalopathy phenotypes" (2019). Department of Biochemistry and Molecular Biology Faculty Papers. Paper 151.
https://jdc.jefferson.edu/bmpfp/151
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
Language
English
Comments
This article has been peer reviewed. It is the author’s final published version in Neurology: Genetics, Volume 5, Issue 2, April 2019, Article number e316.
The published version is available at https://doi.org/10.1212/NXG.0000000000000316. Copyright © Sun et al.