Title: Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy
Authors: Jordanova, Albena
Irobi, Joy
Thomas, Florian P
Van Dijck, Patrick
Meerschaert, Kris
Dewil, Maarten
Dierick, Ines
Jacobs, An
De Vriendt, Els
Guergueltcheva, Velina
Rao, Chitharanjan V
Tournev, Ivailo
Gondim, Francisco A A
D'Hooghe, Marc
Van Gerwen, Veerle
Callaerts, Patrick
Van Den Bosch, Ludo
Timmermans, Jean-Pièrre
Robberecht, Wim
Gettemans, Jan
Thevelein, Johan
De Jonghe, Peter
Kremensky, Ivo
Timmerman, Vincent # ×
Issue Date: Feb-2006
Publisher: Nature America, Inc.
Series Title: Nature Genetics vol:38 issue:2 pages:197-202
Abstract: Charcot-Marie-Tooth (CMT) neuropathies are common disorders of the peripheral nervous system caused by demyelination or axonal degeneration, or a combination of both features. We previously assigned the locus for autosomal dominant intermediate CMT neuropathy type C (DI-CMTC) to chromosome 1p34-p35. Here we identify two heterozygous missense mutations (G41R and E196K) and one de novo deletion (153-156delVKQV) in tyrosyl-tRNA synthetase (YARS) in three unrelated families affected with DI-CMTC. Biochemical experiments and genetic complementation in yeast show partial loss of aminoacylation activity of the mutant proteins, and mutations in YARS, or in its yeast ortholog TYS1, reduce yeast growth. YARS localizes to axonal termini in differentiating primary motor neuron and neuroblastoma cultures. This specific distribution is significantly reduced in cells expressing mutant YARS proteins. YARS is the second aminoacyl-tRNA synthetase found to be involved in CMT, thereby linking protein-synthesizing complexes with neurodegeneration.
ISSN: 1061-4036
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Research Group Experimental Neurology
Molecular Microbiology and Biotechnology Section - miscellaneous
Associated Laboratories - miscellaneous (-)
Laboratory for Neurobiology (Vesalius Research Center)
Department of Human Genetics - miscellaneous
× corresponding author
# (joint) last author

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