Loss-of-function mutations in Lysyl-tRNA synthetase cause various leukoencephalopathy phenotypes

Chong Sun, Jie Song, Yanjun Jiang, Chongbo Zhao, Jiahong Lu, Yuxin Li, Yin Wang, Mingshi Gao, Jianying Xi, Sushan Luo, Meixia Li, Kevin Donaldson, Stephanie N. Oprescu, Thomas P. Slavin, Sansan Lee, Pilar L. Magoulas, Andrea M. Lewis, Lisa Emrick, Seema R. Lalani, Zhiyv NiuMegan L. Landsverk, Magdalena Walkiewicz, Richard E. Person, Hui Mei, Jill A. Rosenfeld, Yaping Yang, Anthony Antonellis, Ya Ming Hou, Jie Lin, Victor W. Zhang

Research output: Contribution to journalArticle

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 defective 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.

Original languageEnglish (US)
Article numbere316
JournalNeurology: Genetics
Volume5
Issue number2
DOIs
StatePublished - Apr 1 2019
Externally publishedYes

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Lysine-tRNA Ligase
Leukoencephalopathies
Phenotype
Mutation
Missense Mutation
Aminoacylation
Exome
Charcot-Marie-Tooth Disease
Microcephaly
Muscle Hypotonia
Aptitude
Insertional Mutagenesis
Vision Disorders
Ataxia
Neuroimaging
Seizures
Yeasts

ASJC Scopus subject areas

  • Clinical Neurology
  • Genetics(clinical)

Cite this

Loss-of-function mutations in Lysyl-tRNA synthetase cause various leukoencephalopathy phenotypes. / 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; Zhang, Victor W.

In: Neurology: Genetics, Vol. 5, No. 2, e316, 01.04.2019.

Research output: Contribution to journalArticle

Sun, C, Song, J, Jiang, Y, Zhao, C, Lu, J, Li, Y, Wang, Y, Gao, M, Xi, J, Luo, S, Li, M, Donaldson, K, Oprescu, SN, Slavin, TP, Lee, S, Magoulas, PL, Lewis, AM, Emrick, L, Lalani, SR, Niu, Z, Landsverk, ML, Walkiewicz, M, Person, RE, Mei, H, Rosenfeld, JA, Yang, Y, Antonellis, A, Hou, YM, Lin, J & Zhang, VW 2019, 'Loss-of-function mutations in Lysyl-tRNA synthetase cause various leukoencephalopathy phenotypes', Neurology: Genetics, vol. 5, no. 2, e316. https://doi.org/10.1212/NXG.0000000000000316
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 ; Zhang, Victor W. / Loss-of-function mutations in Lysyl-tRNA synthetase cause various leukoencephalopathy phenotypes. In: Neurology: Genetics. 2019 ; Vol. 5, No. 2.
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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 defective 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.",
author = "Chong Sun and Jie Song and Yanjun Jiang and Chongbo Zhao and Jiahong Lu and Yuxin Li and Yin Wang and Mingshi Gao and Jianying Xi and Sushan Luo and Meixia Li and Kevin Donaldson and Oprescu, {Stephanie N.} and Slavin, {Thomas P.} and Sansan Lee and Magoulas, {Pilar L.} and Lewis, {Andrea M.} and Lisa Emrick and Lalani, {Seema R.} and Zhiyv Niu and Landsverk, {Megan L.} and Magdalena Walkiewicz and Person, {Richard E.} and Hui Mei and Rosenfeld, {Jill A.} and Yaping Yang and Anthony Antonellis and Hou, {Ya Ming} and Jie Lin and Zhang, {Victor W.}",
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TY - JOUR

T1 - Loss-of-function mutations in Lysyl-tRNA synthetase cause various leukoencephalopathy phenotypes

AU - Sun, Chong

AU - Song, Jie

AU - Jiang, Yanjun

AU - Zhao, Chongbo

AU - Lu, Jiahong

AU - Li, Yuxin

AU - Wang, Yin

AU - Gao, Mingshi

AU - Xi, Jianying

AU - Luo, Sushan

AU - Li, Meixia

AU - Donaldson, Kevin

AU - Oprescu, Stephanie N.

AU - Slavin, Thomas P.

AU - Lee, Sansan

AU - Magoulas, Pilar L.

AU - Lewis, Andrea M.

AU - Emrick, Lisa

AU - Lalani, Seema R.

AU - Niu, Zhiyv

AU - Landsverk, Megan L.

AU - Walkiewicz, Magdalena

AU - Person, Richard E.

AU - Mei, Hui

AU - Rosenfeld, Jill A.

AU - Yang, Yaping

AU - Antonellis, Anthony

AU - Hou, Ya Ming

AU - Lin, Jie

AU - Zhang, Victor W.

PY - 2019/4/1

Y1 - 2019/4/1

N2 - 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 defective 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.

AB - 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 defective 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.

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