A recurrent WARS mutation is a novel cause of autosomal dominant distal hereditary motor neuropathy

Pei Chien Tsai, Bing Wen Soong, Inès Mademan, Yen Hua Huang, Chia Rung Liu, Cheng Tsung Hsiao, Hung Ta Wu, Tze Tze Liu, Yo Tsen Liu, Yen Ting Tseng, Kon Ping Lin, Ueng Cheng Yang, Ki Wha Chung, Byung Ok Choi, Garth A. Nicholson, Marina L. Kennerson, Chih Chiang Chan, Peter De Jonghe, Tzu Hao Cheng, Yi Chu Liao & 3 others Stephan L Zuchner, Jonathan Baets, Yi Chung Lee

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Distal hereditary motor neuropathy is a heterogeneous group of inherited neuropathies characterized by distal limb muscle weakness and atrophy. Although at least 15 genes have been implicated in distal hereditary motor neuropathy, the genetic causes remain elusive in many families. To identify an additional causal gene for distal hereditary motor neuropathy, we performed exome sequencing for two affected individuals and two unaffected members in a Taiwanese family with an autosomal dominant distal hereditary motor neuropathy in which mutations in common distal hereditary motor neuropathy-implicated genes had been excluded. The exome sequencing revealed a heterozygous mutation, c.770A>G (p.His257Arg), in the cytoplasmic tryptophanyl-tRNA synthetase (TrpRS) gene (WARS) that cosegregates with the neuropathy in the family. Further analyses of WARS in an additional 79 Taiwanese pedigrees with inherited neuropathies and 163 index cases from Australian, European, and Korean distal hereditary motor neuropathy families identified the same mutation in another Taiwanese distal hereditary motor neuropathy pedigree with different ancestries and one additional Belgian distal hereditary motor neuropathy family of Caucasian origin. Cell transfection studies demonstrated a dominant-negative effect of the p.His257Arg mutation on aminoacylation activity of TrpRS, which subsequently compromised protein synthesis and reduced cell viability. His257Arg TrpRS also inhibited neurite outgrowth and led to neurite degeneration in the neuronal cell lines and rat motor neurons. Further in vitro analyses showed that the WARS mutation could potentiate the angiostatic activities of TrpRS by enhancing its interaction with vascular endothelial-cadherin. Taken together, these findings establish WARS as a gene whose mutations may cause distal hereditary motor neuropathy and alter canonical and non-canonical functions of TrpRS.

Original languageEnglish (US)
Pages (from-to)1252-1266
Number of pages15
JournalBrain
Volume140
Issue number5
DOIs
StatePublished - May 1 2017

Fingerprint

Tryptophan-tRNA Ligase
Mutation
Exome
Genes
Pedigree
Aminoacylation
Muscular Atrophy
Muscle Weakness
Motor Neurons
Neurites
Transfection
Causes
Distal
Cell Survival
Extremities
Cell Line
Gene

Keywords

  • dHMN
  • distal hereditary motor neuropathy
  • exome sequencing
  • tryptophanyl-tRNA synthetase
  • WARS

ASJC Scopus subject areas

  • Medicine(all)
  • Arts and Humanities (miscellaneous)
  • Clinical Neurology

Cite this

Tsai, P. C., Soong, B. W., Mademan, I., Huang, Y. H., Liu, C. R., Hsiao, C. T., ... Lee, Y. C. (2017). A recurrent WARS mutation is a novel cause of autosomal dominant distal hereditary motor neuropathy. Brain, 140(5), 1252-1266. https://doi.org/10.1093/brain/awx058

A recurrent WARS mutation is a novel cause of autosomal dominant distal hereditary motor neuropathy. / Tsai, Pei Chien; Soong, Bing Wen; Mademan, Inès; Huang, Yen Hua; Liu, Chia Rung; Hsiao, Cheng Tsung; Wu, Hung Ta; Liu, Tze Tze; Liu, Yo Tsen; Tseng, Yen Ting; Lin, Kon Ping; Yang, Ueng Cheng; Chung, Ki Wha; Choi, Byung Ok; Nicholson, Garth A.; Kennerson, Marina L.; Chan, Chih Chiang; De Jonghe, Peter; Cheng, Tzu Hao; Liao, Yi Chu; Zuchner, Stephan L; Baets, Jonathan; Lee, Yi Chung.

In: Brain, Vol. 140, No. 5, 01.05.2017, p. 1252-1266.

Research output: Contribution to journalArticle

Tsai, PC, Soong, BW, Mademan, I, Huang, YH, Liu, CR, Hsiao, CT, Wu, HT, Liu, TT, Liu, YT, Tseng, YT, Lin, KP, Yang, UC, Chung, KW, Choi, BO, Nicholson, GA, Kennerson, ML, Chan, CC, De Jonghe, P, Cheng, TH, Liao, YC, Zuchner, SL, Baets, J & Lee, YC 2017, 'A recurrent WARS mutation is a novel cause of autosomal dominant distal hereditary motor neuropathy', Brain, vol. 140, no. 5, pp. 1252-1266. https://doi.org/10.1093/brain/awx058
Tsai PC, Soong BW, Mademan I, Huang YH, Liu CR, Hsiao CT et al. A recurrent WARS mutation is a novel cause of autosomal dominant distal hereditary motor neuropathy. Brain. 2017 May 1;140(5):1252-1266. https://doi.org/10.1093/brain/awx058
Tsai, Pei Chien ; Soong, Bing Wen ; Mademan, Inès ; Huang, Yen Hua ; Liu, Chia Rung ; Hsiao, Cheng Tsung ; Wu, Hung Ta ; Liu, Tze Tze ; Liu, Yo Tsen ; Tseng, Yen Ting ; Lin, Kon Ping ; Yang, Ueng Cheng ; Chung, Ki Wha ; Choi, Byung Ok ; Nicholson, Garth A. ; Kennerson, Marina L. ; Chan, Chih Chiang ; De Jonghe, Peter ; Cheng, Tzu Hao ; Liao, Yi Chu ; Zuchner, Stephan L ; Baets, Jonathan ; Lee, Yi Chung. / A recurrent WARS mutation is a novel cause of autosomal dominant distal hereditary motor neuropathy. In: Brain. 2017 ; Vol. 140, No. 5. pp. 1252-1266.
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abstract = "Distal hereditary motor neuropathy is a heterogeneous group of inherited neuropathies characterized by distal limb muscle weakness and atrophy. Although at least 15 genes have been implicated in distal hereditary motor neuropathy, the genetic causes remain elusive in many families. To identify an additional causal gene for distal hereditary motor neuropathy, we performed exome sequencing for two affected individuals and two unaffected members in a Taiwanese family with an autosomal dominant distal hereditary motor neuropathy in which mutations in common distal hereditary motor neuropathy-implicated genes had been excluded. The exome sequencing revealed a heterozygous mutation, c.770A>G (p.His257Arg), in the cytoplasmic tryptophanyl-tRNA synthetase (TrpRS) gene (WARS) that cosegregates with the neuropathy in the family. Further analyses of WARS in an additional 79 Taiwanese pedigrees with inherited neuropathies and 163 index cases from Australian, European, and Korean distal hereditary motor neuropathy families identified the same mutation in another Taiwanese distal hereditary motor neuropathy pedigree with different ancestries and one additional Belgian distal hereditary motor neuropathy family of Caucasian origin. Cell transfection studies demonstrated a dominant-negative effect of the p.His257Arg mutation on aminoacylation activity of TrpRS, which subsequently compromised protein synthesis and reduced cell viability. His257Arg TrpRS also inhibited neurite outgrowth and led to neurite degeneration in the neuronal cell lines and rat motor neurons. Further in vitro analyses showed that the WARS mutation could potentiate the angiostatic activities of TrpRS by enhancing its interaction with vascular endothelial-cadherin. Taken together, these findings establish WARS as a gene whose mutations may cause distal hereditary motor neuropathy and alter canonical and non-canonical functions of TrpRS.",
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AU - Hsiao, Cheng Tsung

AU - Wu, Hung Ta

AU - Liu, Tze Tze

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AU - Lin, Kon Ping

AU - Yang, Ueng Cheng

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AU - Choi, Byung Ok

AU - Nicholson, Garth A.

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AU - Chan, Chih Chiang

AU - De Jonghe, Peter

AU - Cheng, Tzu Hao

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N2 - Distal hereditary motor neuropathy is a heterogeneous group of inherited neuropathies characterized by distal limb muscle weakness and atrophy. Although at least 15 genes have been implicated in distal hereditary motor neuropathy, the genetic causes remain elusive in many families. To identify an additional causal gene for distal hereditary motor neuropathy, we performed exome sequencing for two affected individuals and two unaffected members in a Taiwanese family with an autosomal dominant distal hereditary motor neuropathy in which mutations in common distal hereditary motor neuropathy-implicated genes had been excluded. The exome sequencing revealed a heterozygous mutation, c.770A>G (p.His257Arg), in the cytoplasmic tryptophanyl-tRNA synthetase (TrpRS) gene (WARS) that cosegregates with the neuropathy in the family. Further analyses of WARS in an additional 79 Taiwanese pedigrees with inherited neuropathies and 163 index cases from Australian, European, and Korean distal hereditary motor neuropathy families identified the same mutation in another Taiwanese distal hereditary motor neuropathy pedigree with different ancestries and one additional Belgian distal hereditary motor neuropathy family of Caucasian origin. Cell transfection studies demonstrated a dominant-negative effect of the p.His257Arg mutation on aminoacylation activity of TrpRS, which subsequently compromised protein synthesis and reduced cell viability. His257Arg TrpRS also inhibited neurite outgrowth and led to neurite degeneration in the neuronal cell lines and rat motor neurons. Further in vitro analyses showed that the WARS mutation could potentiate the angiostatic activities of TrpRS by enhancing its interaction with vascular endothelial-cadherin. Taken together, these findings establish WARS as a gene whose mutations may cause distal hereditary motor neuropathy and alter canonical and non-canonical functions of TrpRS.

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