Loss of function mutations in HARS cause a spectrum of inherited peripheral neuropathies

Dana Safka Brozkova, Tine Deconinck, Laurie Beth Griffin, Andreas Ferbert, Jana Haberlova, Radim Mazanec, Petra Lassuthova, Christian Roth, Thanita Pilunthanakul, Bernd Rautenstrauss, Andreas R. Janecke, Petra Zavadakova, Roman Chrast, Carlo Rivolta, Stephan L Zuchner, Anthony Antonellis, Asim A. Beg, Peter De Jonghe, Jan Senderek, Pavel Seeman & 1 others Jonathan Baets

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Inherited peripheral neuropathies are a genetically heterogeneous group of disorders characterized by distal muscle weakness and sensory loss. Mutations in genes encoding aminoacyl-tRNA synthetases have been implicated in peripheral neuropathies, suggesting that these tRNA charging enzymes are uniquely important for the peripheral nerve. Recently, a mutation in histidyl-tRNA synthetase (HARS) was identified in a single patient with a late-onset, sensory-predominant peripheral neuropathy; however, the genetic evidence was lacking, making the significance of the finding unclear. Here, we present clinical, genetic, and functional data that implicate HARS mutations in inherited peripheral neuropathies. The associated phenotypic spectrum is broad and encompasses axonal and demyelinating motor and sensory neuropathies, including four young patients presenting with pure motor axonal neuropathy. Genome-wide linkage studies in combination with whole-exome and conventional sequencing revealed four distinct and previously unreported heterozygous HARS mutations segregating with autosomal dominant peripheral neuropathy in four unrelated families (p.Thr132Ile, p.Pro134His, p.Asp175Glu and p.Asp364Tyr). All mutations cause a loss of function in yeast complementation assays, and p.Asp364Tyr is dominantly neurotoxic in a Caenorhabditis elegans model. This study demonstrates the role of HARS mutations in peripheral neuropathy and expands the genetic and clinical spectrum of aminoacyl-tRNA synthetase-related human disease.

Original languageEnglish (US)
Pages (from-to)2161-2172
Number of pages12
JournalBrain
Volume138
Issue number8
DOIs
StatePublished - Aug 1 2015

Fingerprint

Peripheral Nervous System Diseases
Mutation
Amino Acyl-tRNA Synthetases
Histidine-tRNA Ligase
Transfer RNA Aminoacylation
Exome
Muscle Weakness
Caenorhabditis elegans
Peripheral Nerves
Inherited Peripheral Neuropathy
Causes
Yeasts
Genome
Enzymes
Genes

Keywords

  • hereditary motor and sensory neuropathies
  • molecular genetics
  • neurodegeneration
  • RNA processing
  • whole-exome sequencing

ASJC Scopus subject areas

  • Clinical Neurology
  • Arts and Humanities (miscellaneous)

Cite this

Safka Brozkova, D., Deconinck, T., Beth Griffin, L., Ferbert, A., Haberlova, J., Mazanec, R., ... Baets, J. (2015). Loss of function mutations in HARS cause a spectrum of inherited peripheral neuropathies. Brain, 138(8), 2161-2172. https://doi.org/10.1093/brain/awv158

Loss of function mutations in HARS cause a spectrum of inherited peripheral neuropathies. / Safka Brozkova, Dana; Deconinck, Tine; Beth Griffin, Laurie; Ferbert, Andreas; Haberlova, Jana; Mazanec, Radim; Lassuthova, Petra; Roth, Christian; Pilunthanakul, Thanita; Rautenstrauss, Bernd; Janecke, Andreas R.; Zavadakova, Petra; Chrast, Roman; Rivolta, Carlo; Zuchner, Stephan L; Antonellis, Anthony; Beg, Asim A.; De Jonghe, Peter; Senderek, Jan; Seeman, Pavel; Baets, Jonathan.

In: Brain, Vol. 138, No. 8, 01.08.2015, p. 2161-2172.

Research output: Contribution to journalArticle

Safka Brozkova, D, Deconinck, T, Beth Griffin, L, Ferbert, A, Haberlova, J, Mazanec, R, Lassuthova, P, Roth, C, Pilunthanakul, T, Rautenstrauss, B, Janecke, AR, Zavadakova, P, Chrast, R, Rivolta, C, Zuchner, SL, Antonellis, A, Beg, AA, De Jonghe, P, Senderek, J, Seeman, P & Baets, J 2015, 'Loss of function mutations in HARS cause a spectrum of inherited peripheral neuropathies', Brain, vol. 138, no. 8, pp. 2161-2172. https://doi.org/10.1093/brain/awv158
Safka Brozkova D, Deconinck T, Beth Griffin L, Ferbert A, Haberlova J, Mazanec R et al. Loss of function mutations in HARS cause a spectrum of inherited peripheral neuropathies. Brain. 2015 Aug 1;138(8):2161-2172. https://doi.org/10.1093/brain/awv158
Safka Brozkova, Dana ; Deconinck, Tine ; Beth Griffin, Laurie ; Ferbert, Andreas ; Haberlova, Jana ; Mazanec, Radim ; Lassuthova, Petra ; Roth, Christian ; Pilunthanakul, Thanita ; Rautenstrauss, Bernd ; Janecke, Andreas R. ; Zavadakova, Petra ; Chrast, Roman ; Rivolta, Carlo ; Zuchner, Stephan L ; Antonellis, Anthony ; Beg, Asim A. ; De Jonghe, Peter ; Senderek, Jan ; Seeman, Pavel ; Baets, Jonathan. / Loss of function mutations in HARS cause a spectrum of inherited peripheral neuropathies. In: Brain. 2015 ; Vol. 138, No. 8. pp. 2161-2172.
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AU - Mazanec, Radim

AU - Lassuthova, Petra

AU - Roth, Christian

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AU - Janecke, Andreas R.

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AU - Chrast, Roman

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AU - Zuchner, Stephan L

AU - Antonellis, Anthony

AU - Beg, Asim A.

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N2 - Inherited peripheral neuropathies are a genetically heterogeneous group of disorders characterized by distal muscle weakness and sensory loss. Mutations in genes encoding aminoacyl-tRNA synthetases have been implicated in peripheral neuropathies, suggesting that these tRNA charging enzymes are uniquely important for the peripheral nerve. Recently, a mutation in histidyl-tRNA synthetase (HARS) was identified in a single patient with a late-onset, sensory-predominant peripheral neuropathy; however, the genetic evidence was lacking, making the significance of the finding unclear. Here, we present clinical, genetic, and functional data that implicate HARS mutations in inherited peripheral neuropathies. The associated phenotypic spectrum is broad and encompasses axonal and demyelinating motor and sensory neuropathies, including four young patients presenting with pure motor axonal neuropathy. Genome-wide linkage studies in combination with whole-exome and conventional sequencing revealed four distinct and previously unreported heterozygous HARS mutations segregating with autosomal dominant peripheral neuropathy in four unrelated families (p.Thr132Ile, p.Pro134His, p.Asp175Glu and p.Asp364Tyr). All mutations cause a loss of function in yeast complementation assays, and p.Asp364Tyr is dominantly neurotoxic in a Caenorhabditis elegans model. This study demonstrates the role of HARS mutations in peripheral neuropathy and expands the genetic and clinical spectrum of aminoacyl-tRNA synthetase-related human disease.

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