Funding transnational collaborative research through joint transnational calls is one of the major objectives of E-Rare. This is the most important and effective joint activity to enhance the cooperation between European scientists working on rare diseases and thus reducing the fragmentation of research in this field. E-Rare launches calls on a yearly basis. The topic and eligibility criteria are specified every year and therefore may vary from one call to the other.

MTM1 and MTMR2 myotubularins: biochemical activity and the regulation of membrane trafficking in health and disease

Project Coordinator

Fondazione Centro San Raffaele del Monte Tabor DIBIT


Jocelyn Laporte IGBMC-ISERM U596 - UMR7104 Université Louis Pasteur Department of Molecular Biology Illkrich, France
Mikael Simons Department of Neurology University of Göttingen Göttingen, Germany

Publications of the MTMpathies2 project

Major results of the project

Myotubularins represent a large family of proteins with several members mutated in different neuromuscular disorders: demyelinating Charcot-Marie-Tooth (CMT) type 4B neuropathies (MTMR2 and MTMR13) and congenital myotubular/centronuclear myopathy (MTM1). These rare diseases are characterized by early onset and abnormal myelination or disorganization of skeletal muscle fibers, respectively. MTM1 and MTMR2 are lipid phosphatases with a suggested role on the regulation of membrane trafficking. We have previously validated genetic in vitro and in vivo models of the diseases, and we identified several protein partners, which have been extensively explored. Despite these findings, however, the cellular events regulated by MTM1 and MTMR2 and whether the phosphatase activity mediates MTM1 and MTMR2 biological function still remain to be clarified.

This project added relevant information on the pathogenesis of the CMT4B1. In particular, we showed that altered trafficking events and/or cytoskeleton remodeling controlled by the PtdIns(3,5)P2 lipid are at the basis of the excessive longitudinal myelin elongation and myelin outfoldings, hallmark of the CMT4B1 neuropathy. We propose that the pharmacological downregulation of PtdIns(3,5)P2 levels may constitute a therapeutic strategy for CMT4B1. We also investigated the role of PtdIns(3,5)P2 metabolism in the regulation of myelination and regeneration in the peripheral nervous system. We also showed that MTM1 localizes at cellular structure regulating intracellular calcium release triggering muscle contraction.
MTM1 loss is associated to defect in autophagy, the mechanism regulating the turn-over of cellular components; this defect appears as a primary cause of the myotubular/centronuclear myopathy pathogenesis. Finally, downregulation of DNM2, a protein also mutated in centronuclear myopathy, strongly prevents disease progression in a mouse model of myotubular myopathy. These data identified DNM2 as an important therapeutic target

E-Rare 2012 - Created by Toussaint Biger