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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Increased titers of antibodies to GM1 ganglioside in humans are associated with lower motor neuron disease and predominantly motor neuropathy with or without conduction block. To investigate the possible mechanism of these antibodies, we injected the serum of a patient with anti-GM1 antibodies who had motor neuron disease and multifocal motor conduction block, into rat sciatic nerve. When injected with fresh human complement, the serum-induced conduction block with temporal dispersion and deposits of immunoglobulin were detected at the nodes of Ranvier. Electron microscopic studies revealed demyelination in 6.5% of the fibers. After preabsorption with GM1, the serum had no effect, suggesting that the anti-GM1 antibodies were responsible for the conduction abnormalities.

Charcot-Marie-Tooth disease (CMT) is a length-dependent peripheral neuropathy. The aminoacyl-tRNA synthetases constitute the largest protein family implicated in CMT. Aminoacyl-tRNA synthetases are predominantly cytoplasmic, but are also present in the nucleus. Here we show that a nuclear function of tyrosyl-tRNA synthetase (TyrRS) is implicated in a Drosophila model of CMT. CMT-causing mutations in TyrRS induce unique conformational changes, which confer capacity for aberrant interactions with transcriptional regulators in the nucleus, leading to transcription factor E2F1 hyperactivation. Using neuronal tissues, we reveal a broad transcriptional regulation network associated with wild-type TyrRS expression, which is disturbed when a CMT-mutant is expressed. Pharmacological inhibition of TyrRS nuclear entry with embelin reduces, whereas genetic nuclear exclusion of mutant TyrRS prevents hallmark phenotypes of CMT in the Drosophila model. These data highlight that this translation factor may contribute to transcriptional regulation in neurons, and suggest a therapeutic strategy for CMT.

Fairly high levels of computer and Internet use exist among veterans with SCI/D. Veterans with SCI/D also have a strong preference for people-particularly health professionals, and to a lesser extent peers and family and friends-as sources of information about SCI/D. These findings highlight the importance of combining technology and human interaction to meet the information needs of this population.

Dominant intermediate Charcot-Marie-Tooth (DI-CMT) neuropathy is a genetic and phenotypic variant of classical CMT, characterized by intermediate nerve conduction velocities and histological evidence of both axonal and demyelinating features. We report two unrelated families with intermediate CMT linked to a novel locus on chromosome 1p34-p35 (DI-CMTC). The combined haplotype analysis in both families localized the DI-CMTC gene within a 6.3-cM linkage interval flanked by markers D1S2787 and D1S2830. The functional and positional candidate genes, Syndecan 3 (SDC3), and lysosomal-associated multispanning membrane protein 5 (LAPTM5) were excluded for pathogenic mutations.

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