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

Safka Brozkova, Dana and Deconinck, Tine and Griffin, Laurie Beth and Ferbert, Andreas and Haberlova, Jana and Mazanec, Radim and Lassuthova, Petra and Roth, Christian and Pilunthanakul, Thanita and Rautenstrauss, Bernd and Janecke, Andreas R. and Zavadakova, Petra and Chrast, Roman and Rivolta, Carlo and Zuchner, Stephan and Antonellis, Anthony and Beg, Asim A. and De Jonghe, Peter and Senderek, Jan and Seeman, Pavel and Baets, Jonathan. (2015) Loss of function mutations in HARS cause a spectrum of inherited peripheral neuropathies. Brain, 138 (8). pp. 2161-2172.

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Official URL: https://edoc.unibas.ch/81713/

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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.
Faculties and Departments:03 Faculty of Medicine
09 Associated Institutions > Institute of Molecular and Clinical Ophthalmology Basel (IOB)
UniBasel Contributors:Rivolta, Carlo
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Oxford University Press
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:03 Mar 2021 12:58
Deposited On:03 Mar 2021 12:58

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