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SH3TC2, a protein mutant in Charcot–Marie–Tooth neuropathy, links peripheral nerve myelination to endosomal recycling

Claudia Stendel, Andreas Roos, Henning Kleine, Estelle Arnaud, Murat Özçelik, Páris N. M. Sidiropoulos, Jennifer Zenker, Fanny Schüpfer, Ute Lehmann, Radoslaw M. Sobota, David W. Litchfield, Bernhard Lüscher, Roman Chrast, Ueli Suter, Jan Senderek
DOI: http://dx.doi.org/10.1093/brain/awq168 2462-2474 First published online: 26 July 2010


Patients with Charcot–Marie–Tooth neuropathy and gene targeting in mice revealed an essential role for the SH3TC2 gene in peripheral nerve myelination. SH3TC2 expression is restricted to Schwann cells in the peripheral nervous system, and the gene product, SH3TC2, localizes to the perinuclear recycling compartment. Here, we show that SH3TC2 interacts with the small guanosine triphosphatase Rab11, which is known to regulate the recycling of internalized membranes and receptors back to the cell surface. Results of protein binding studies and transferrin receptor trafficking are in line with a role of SH3TC2 as a Rab11 effector molecule. Consistent with a function of Rab11 in Schwann cell myelination, SH3TC2 mutations that cause neuropathy disrupt the SH3TC2/Rab11 interaction, and forced expression of dominant negative Rab11 strongly impairs myelin formation in vitro. Our data indicate that the SH3TC2/Rab11 interaction is relevant for peripheral nerve pathophysiology and place endosomal recycling on the list of cellular mechanisms involved in Schwann cell myelination.

  • SH3TC2 / KIAA1985
  • Rab11
  • recycling endosome
  • Schwann cell myelination
  • Charcot-Marie-Tooth neuropathy
  • Abbreviations:
    Charcot–Marie–Tooth neuropathy type 4C
    diamidino-2-phenylindole dihydrochloride
    Dulbecco’s modified Eagle’s medium
    green fluorescent protein
    glutathione S-transferase
    phosphate buffered saline
    peripheral nervous system
    sodium dodecyl sulphate–polyacrylamide gel electrophoresis
    Src homology 3 domain and tetratricopeptide repeats 2
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