Charcot-Marie-Tooth (CMT) disease is the most common inherited demyelinating disorder affecting the peripheral nervous system (PNS).  Despite the fact that the genes that are mutated in different forms of CMT have been identified, the pathogenesis of the disease is still largely unknown and there are currently no effective treatments to stop the progression of myelin loss.  This is in part due to our limited understanding of the cell biology of myelination. 

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CMT4B is caused by loss-of-function mutations in a gene coding for Mtmr2, a phosphatase that is involved in phosphoinositide biosynthesis.  Patients with CMT4B exhibit myelin abnormalities in the PNS including demyelination as well as myelin overproduction, suggesting that the mutation affects myelin homeostasis.  Mtmr2 and the lipd product PI(3,5)P2 is localized to late endosome and lysosome, indicating that Mtmr2 may play a role in regulating endo-lysosomal trafficking and/or the associated signaling.  In fact, our data show that loss of Mtmr2 in Schwann cells resutls in aberrant increase in lysosome-associated mTOR activity, which has been shown to regulate myelin production.  Currently, we are using in vitro myelinating culture system combined with molecular and cellular approaches to elucidate the efficacy of Mtmr2 knock-down on myelin homeostasis.