The TRK-Fused Gene Is Mutated in Hereditary Motor and Sensory Neuropathy with Proximal Dominant Involvement

摘要: Hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) is an autosomal-dominant neurodegenerative disorder characterized by widespread fasciculations, proximal-predominant muscle weakness, atrophy followed distal involvement. To date, large families affected HMSN-P have been reported from two different regions in Japan. Linkage haplotype analyses of previously new the use high-density SNP arrays further defined minimum candidate region 3.3 Mb chromosomal 3q12. Exome sequencing showed identical c.854C>T (p.Pro285Leu) mutation TRK-fused gene (TFG) four families. Detailed analysis suggested independent origins mutation. Pathological studies autopsied patient revealed TFG- ubiquitin-immunopositive cytoplasmic inclusions spinal cortical neurons. Fragmentation Golgi apparatus, a frequent finding amyotrophic lateral sclerosis, was also observed neurons inclusion bodies. Moreover, TAR DNA-binding protein 43 kDa (TDP-43)-positive were demonstrated. In cultured cells expressing mutant TFG, aggregation TDP-43 These findings indicate that formation TFG-containing concomitant mislocalization underlie neuron degeneration HMSN-P. overlap proteinopathies involving TFG highlights pathway leading to degeneration.