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 language | English (US) |
|---|---|
| Pages (from-to) | 2161-2172 |
| Number of pages | 12 |
| Journal | Brain |
| Volume | 138 |
| Issue number | 8 |
| DOIs | |
| State | Published - Aug 1 2015 |
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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
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 journal › Article
}
TY - JOUR
T1 - Loss of function mutations in HARS cause a spectrum of inherited peripheral neuropathies
AU - Safka Brozkova, Dana
AU - Deconinck, Tine
AU - Beth Griffin, Laurie
AU - Ferbert, Andreas
AU - Haberlova, Jana
AU - Mazanec, Radim
AU - Lassuthova, Petra
AU - Roth, Christian
AU - Pilunthanakul, Thanita
AU - Rautenstrauss, Bernd
AU - Janecke, Andreas R.
AU - Zavadakova, Petra
AU - Chrast, Roman
AU - Rivolta, Carlo
AU - Zuchner, Stephan L
AU - Antonellis, Anthony
AU - Beg, Asim A.
AU - De Jonghe, Peter
AU - Senderek, Jan
AU - Seeman, Pavel
AU - Baets, Jonathan
PY - 2015/8/1
Y1 - 2015/8/1
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.
AB - 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.
KW - hereditary motor and sensory neuropathies
KW - molecular genetics
KW - neurodegeneration
KW - RNA processing
KW - whole-exome sequencing
UR - http://www.scopus.com/inward/record.url?scp=84940061601&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84940061601&partnerID=8YFLogxK
U2 - 10.1093/brain/awv158
DO - 10.1093/brain/awv158
M3 - Article
VL - 138
SP - 2161
EP - 2172
JO - Brain
JF - Brain
SN - 0006-8950
IS - 8
ER -