Missense mutations in the SH3TC2 protein causing Charcot-Marie-Tooth disease type 4C affect its localization in the plasma membrane and endocytic pathway

32 p., figuras y bibliografía
Mutations in SH3TC2 cause Charcot-Marie Tooth disease (CMT) type 4C, a demyelinating inherited neuropathy characterized by early onset and scoliosis. Here we demonstrate that SH3TC2 is expressed in several components of the endocytic pathway including early endosomes, late endosomes and clathrin-coated vesicles close to the trans-Golgi network, and in the plasma membrane. Myristoylation of SH3TC2 in glycine 2 is necessary but not sufficient for the proper location of the protein in the cell membranes. In addition to myristoylation, correct anchoring also needs the presence of SH3 and TPR domains. Mutations that cause a stop codon and produce premature truncations that remove most of the TPR domains are expressed as the wild type protein. In contrast, missense mutations in or around the region of the first TPR domain are not expressed in early endosomes, have reduced expression in plasma membrane and late endosomes, and are variably expressed in clathrin-coated vesicles. Our findings suggest that the endocytic and membrane trafficking pathway is involved in the pathogenesis of CMT4C disease. We postulate that missense mutations of SH3TC2 could impair communication between the Schwann cell and the axon causing an abnormal myelin formation.
This work was supported by the Fondo de Investigación Sanitaria [grant numbers PI08/90857, PI08/0889, CP08/00053] and the Spanish Ministry Science and Innovation [grant number SAF2006-01047]. V. L. is a recipient of JAE predoctoral fellowship from the Spanish National Research Council (CSIC). M.I.G. has a “Ramón y Cajal” contract funded by the Ministry of Science and Innovation. C.E. has a “Miguel Servet” contract funded by the Fondo de Investigación Sanitaria. Both CIBERER and CIBERNED are initiatives from the Instituto de Salud Carlos III.