2. Academic Validation
  3. Loss of function mutations in HARS cause a spectrum of inherited peripheral neuropathies

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

  • Brain. 2015 Aug;138(Pt 8):2161-72. doi: 10.1093/brain/awv158.
Dana Safka Brozkova 1,  Tine Deconinck 2,  Laurie Beth Griffin 3,  Andreas Ferbert 4,  Jana Haberlova 1,  Radim Mazanec 5,  Petra Lassuthova 1,  Christian Roth 4,  Thanita Pilunthanakul 6,  Bernd Rautenstrauss 7,  Andreas R Janecke 8,  Petra Zavadakova 9,  Roman Chrast 9,  Carlo Rivolta 9,  Stephan Zuchner 10,  Anthony Antonellis 11,  Asim A Beg 6,  Peter De Jonghe 12,  Jan Senderek 13,  Pavel Seeman 14,  Jonathan Baets 12
Affiliations

Affiliations

  • 1 1 DNA Laboratory, Department of Paediatric Neurology, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague 150 06, Czech Republic.
  • 2 2 Neurogenetics Group, VIB-Department of Molecular Genetics, University of Antwerp, Antwerpen 2610, Belgium 3 Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerpen 2610, Belgium.
  • 3 4 Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI-48109, USA 5 Medical Scientist Training Program, University of Michigan Medical School, Ann Arbor, MI-48109, USA.
  • 4 6 Department of Neurology, Klinikum Kassel, Kassel 34125, Germany.
  • 5 7 Department of Neurology, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague 150 06, Czech Republic.
  • 6 8 Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI-48109, USA.
  • 7 9 Medizinisch Genetisches Zentrum, Munich 80335, Germany 10 Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University, Munich 80336, Germany.
  • 8 11 Division of Human Genetics and Department of Pediatrics I, Medical University of Innsbruck, Innsbruck 6020, Austria.
  • 9 12 Department of Medical Genetics, University of Lausanne, Lausanne 1005, Switzerland.
  • 10 13 Dr John T McDonald Foundation Department of Human Genetics, John P Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL-33136, USA.
  • 11 4 Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI-48109, USA 14 Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI-48109, USA 15 Department of Neurology, University of Michigan Medical School, Ann Arbor, MI-48109, USA.
  • 12 2 Neurogenetics Group, VIB-Department of Molecular Genetics, University of Antwerp, Antwerpen 2610, Belgium 3 Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerpen 2610, Belgium 16 Department of Neurology, Antwerp University Hospital, Antwerpen 2610, Belgium.
  • 13 10 Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University, Munich 80336, Germany.
  • 14 1 DNA Laboratory, Department of Paediatric Neurology, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague 150 06, Czech Republic pseeman@yahoo.com.
PMID: 26072516 DOI: 10.1093/brain/awv158
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.

Keywords

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

Figures