Jordanova et al. (2003) reported 2 unrelated families with autosomal dominant intermediate Charcot-Marie-Tooth disease. One family, American with German and Polish roots, contained 15 affected individuals over 4 generations. Age at onset was in the first and second ... Jordanova et al. (2003) reported 2 unrelated families with autosomal dominant intermediate Charcot-Marie-Tooth disease. One family, American with German and Polish roots, contained 15 affected individuals over 4 generations. Age at onset was in the first and second decades, with distal leg and arm weakness and numbness. Motor nerve conduction velocities (NCV) ranged from 30-40 m/s. Sural nerve biopsies showed clusters of regenerating fibers and reduction in fiber density and myelin thickness, but no onion bulb formations. The second family, from Bulgaria, had 19 affected members over 7 generations traced back to 1850. Disease onset ranged from 7 to 59 years, and motor symptoms and lower limb involvement predominated. Motor NCVs ranged from 33 m/s to normal.
In the American family described by Jordanova et al. (2003), Jordanova et al. (2006) found a missense mutation in the YARS gene (G41R; 603623.0001). In the Bulgarian family they found a different missense mutation (E196K; 603623.0002), and in ... In the American family described by Jordanova et al. (2003), Jordanova et al. (2006) found a missense mutation in the YARS gene (G41R; 603623.0001). In the Bulgarian family they found a different missense mutation (E196K; 603623.0002), and in an affected individual from Belgium they found an in-frame deletion (603623.0003). Biochemical experiments and genetic complementation in yeast showed partial loss of aminoacylation activity of the mutant proteins, and mutations in YARS, or in its yeast ortholog TYS1, reduced yeast growth. YARS localized to axonal termini in differentiating primary motor neuron and neuroblastoma cultures. This specific distribution is significantly reduced in cells expressing mutant YARS proteins. YARS was the second aminoacyl-tRNA synthetase found to be involved in Charcot-Marie-Tooth disease, thereby linking protein-synthesizing complexes with neurodegeneration. Dominant mutations in GARS, which encodes glycyl-tRNA synthetase (600287), had been found in type 2D Charcot-Marie-Tooth disease (601472) and in distal spinal muscular atrophy type VA (DSMAVA; 600794).