Author:

Keywords:

Amino Acid Sequence, Animals, Axons, Biological Assay, COS Cells, Cell Line, Tumor, Cells, Cultured, Cercopithecus aethiops, Charcot-Marie-Tooth Disease, Genes, Dominant, Genetic Complementation Test, Heterozygote, Humans, Mice, Molecular Sequence Data, Mutation, Protein Transport, Recombinant Proteins, Research Support, Non-U.S. Gov't, Saccharomyces cerevisiae, Sequence Alignment, Tyrosine-tRNA Ligase, Science & Technology, Life Sciences & Biomedicine, Genetics & Heredity, PROTEIN-PROTEIN INTERACTIONS, SITE-DIRECTED MUTAGENESIS, AMINO-ACID, ENZYME STRUCTURE, CYTOKINE, DISEASE, LOCALIZATION, TRANSLATION, MUTATIONS, HOMOLOGY, Chlorocebus aethiops, 06 Biological Sciences, 11 Medical and Health Sciences, Developmental Biology, 3001 Agricultural biotechnology, 3102 Bioinformatics and computational biology, 3105 Genetics

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.