title: Loss of function mutations in HARS cause a spectrum of inherited peripheral neuropathies.
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.
authors.affiliation: 1 DNA Laboratory, Department of Paediatric Neurology, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague 150 06, Czech Republic.
authors.forename: Dana
authors.initials: D
authors.lastname: Safka Brozkova
authors.affiliation: 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.
authors.forename: Tine
authors.initials: T
authors.lastname: Deconinck
authors.affiliation: 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.
authors.forename: Laurie Beth
authors.initials: LB
authors.lastname: Griffin
authors.affiliation: 6 Department of Neurology, Klinikum Kassel, Kassel 34125, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Ferbert
authors.affiliation: 1 DNA Laboratory, Department of Paediatric Neurology, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague 150 06, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Haberlova
authors.affiliation: 7 Department of Neurology, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague 150 06, Czech Republic.
authors.forename: Radim
authors.initials: R
authors.lastname: Mazanec
authors.affiliation: 1 DNA Laboratory, Department of Paediatric Neurology, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague 150 06, Czech Republic.
authors.forename: Petra
authors.initials: P
authors.lastname: Lassuthova
authors.affiliation: 6 Department of Neurology, Klinikum Kassel, Kassel 34125, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Roth
authors.affiliation: 8 Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI-48109, USA.
authors.forename: Thanita
authors.initials: T
authors.lastname: Pilunthanakul
authors.affiliation: 9 Medizinisch Genetisches Zentrum, Munich 80335, Germany 10 Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University, Munich 80336, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Rautenstrauss
authors.affiliation: 11 Division of Human Genetics and Department of Pediatrics I, Medical University of Innsbruck, Innsbruck 6020, Austria.
authors.forename: Andreas R
authors.initials: AR
authors.lastname: Janecke
authors.affiliation: 12 Department of Medical Genetics, University of Lausanne, Lausanne 1005, Switzerland.
authors.forename: Petra
authors.initials: P
authors.lastname: Zavadakova
authors.affiliation: 12 Department of Medical Genetics, University of Lausanne, Lausanne 1005, Switzerland.
authors.forename: Roman
authors.initials: R
authors.lastname: Chrast
authors.affiliation: 12 Department of Medical Genetics, University of Lausanne, Lausanne 1005, Switzerland.
authors.forename: Carlo
authors.initials: C
authors.lastname: Rivolta
authors.affiliation: 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.
authors.forename: Stephan
authors.initials: S
authors.lastname: Zuchner
authors.affiliation: 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.
authors.forename: Anthony
authors.initials: A
authors.lastname: Antonellis
authors.affiliation: 8 Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI-48109, USA.
authors.forename: Asim A
authors.initials: AA
authors.lastname: Beg
authors.affiliation: 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.
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
authors.affiliation: 10 Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University, Munich 80336, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Senderek
authors.affiliation: 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.
authors.forename: Pavel
authors.initials: P
authors.lastname: Seeman
authors.affiliation: 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.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Baets
mesh_terms: D002607:Charcot-Marie-Tooth Disease / Q000235:genetics; D005260:Female; D008040:Genetic Linkage / Q000235:genetics*; D009477:Hereditary Sensory and Autonomic Neuropathies / Q000235:genetics*; D006643:Histidine-tRNA Ligase / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010523:Peripheral Nervous System Diseases / Q000235:genetics*
chemical_list: D006643:Histidine-tRNA Ligase
keywords: RNA processing; hereditary motor and sensory neuropathies; molecular genetics; neurodegeneration; whole-exome sequencing