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Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy


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.

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Figure 1: Mutations in human YARS associated with DI-CMTC.
Figure 2: Pyrophosphate release assay.
Figure 3: Genetic complementation and growth tests in S. cerevisiae.
Figure 4: Cellular distribution of aminoacyl-tRNA synthetases, synaptophysin and neurofilaments.
Figure 5: Confocal images of N2a cells transiently transfected with wild-type and mutant YARS constructs.

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We acknowledge the cooperation and participation of all patients and their relatives in this study. We thank the VIB Genetic Service Facility for genotyping and sequencing; C. Van Broeckhoven for support; V. De Corte and D. Adriaensen for discussions; J. Van Daele and D. De Rijck for assistance with confocal microscopy; C. Coun, C. Colombo and E. Vanderheyden for help with the yeast experiments; and B. Ishpekova and I. Litvinenko for clinical evaluation of the patients. This study was supported by the National Science Fund of the Bulgarian Ministry of Education and Science; the Fund for Scientific Research – Flanders (FWO); the Medical Foundation Queen Elisabeth; the Universities of Antwerp, Leuven and Ghent; and the Interuniversity Attraction Poles program of the Belgian Federal Science Office (POD). Additional support was provided by the Muscular Dystrophy Association (to A.J. and V.T.), the Neuropathy Association (to F.P.T.), the Association Belge contre les Maladies Neuromusculaires (to V.T.) and the Specific Support Action program of the European Union (to A.J. and I.K.). A.J. received visiting research fellowships from the POD and the North Atlantic Treaty Organisation/FWO. J.I. and K.M. are postdoctoral fellows of the FWO, and I.D. is a PhD fellow of the Institute for Science and Technology, Belgium.

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Correspondence to Vincent Timmerman.

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Supplementary information

Supplementary Fig. 1

Heterodimerization between wild-type and mutant YARS isoforms. (PDF 108 kb)

Supplementary Fig. 2

Distribution of synaptophysin, mitochondria and α-tubulin in transfected N2a cells. (PDF 125 kb)

Supplementary Fig. 3

Western blot analysis of YARS. (PDF 211 kb)

Supplementary Methods (PDF 65 kb)

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Jordanova, A., Irobi, J., Thomas, F. et al. Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy. Nat Genet 38, 197–202 (2006).

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