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.

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

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

Department of Medical Genetics University of Lausanne Lausanne 1005 Switzerland

Department of Neurology 2nd Faculty of Medicine Charles University Prague and Motol University Hospital Prague 150 06 Czech Republic

Department of Neurology Klinikum Kassel Kassel 34125 Germany

Department of Pharmacology University of Michigan Medical School Ann Arbor MI 48109 USA

Division of Human Genetics and Department of Pediatrics 1 Medical University of Innsbruck Innsbruck 6020 Austria

DNA Laboratory Department of Paediatric Neurology 2nd Faculty of Medicine Charles University Prague and Motol University Hospital Prague 150 06 Czech Republic

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

Friedrich Baur Institute Department of Neurology Ludwig Maximilians University Munich 80336 Germany

Medizinisch Genetisches Zentrum Munich 80335 Germany 10 Friedrich Baur Institute Department of Neurology Ludwig Maximilians University Munich 80336 Germany

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

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

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