Human Molecular Genetics Advance Access originally published online on September 10, 2009
Human Molecular Genetics 2009 18(23):4603-4614; doi:10.1093/hmg/ddp427
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Missense mutations in the SH3TC2 protein causing Charcot-Marie-Tooth disease type 4C affect its localization in the plasma membrane and endocytic pathway
1 Genetics and Molecular Medicine Unit, Instituto de Biomedicina de Valencia (IBV), CSIC, Valencia 46010, Spain, 2 CIBER de Enfermedades Raras (CIBERER), Valencia 46010, Spain, 3 Neurology Service, Hospital Universitari La Fe, Valencia 46009, Spain and 4 CIBER de Enfermedades Neurodegenerativas (CIBERNED), Valencia 46009, Spain
* To whom correspondence should be addressed at: Genetics and Molecular Medicine Unit, Instituto de Biomedicina de Valencia (IBV), CSIC, c/Jaume Roig, 11, Valencia 46010, Spain. Tel: +34 963393773; Fax: +34 963690800; Email: fpalau{at}ibv.csic.es
Received July 8, 2009; Accepted September 3, 2009
Mutations in SH3TC2 (KIAA1985) cause Charcot-Marie-Tooth disease (CMT) type 4C, a demyelinating inherited neuropathy characterized by early-onset and scoliosis. Here we demonstrate that the SH3TC2 protein is present 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 absent from early endosomes, reduced in plasma membrane and late endosomes and are variably present 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.