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.

Myotubularinopathies: common molecular mechanism and tissue specificity

Project Coordinator

IGBMC-ISERM U596 - UMR7104 Université Louis Pasteur Department of Molecular Biology


Alessandra Bolino Fondazione Centro San Raffaele del Monte Tabor DIBIT Milano, Italy
Bernard Payrastre ISERM U563 - CPTP - IFT30 Université Paul Sabatier Toulouse, France

Myotubularins (MTMs) define a large family of proteins with several members mutated in different neuromuscular disorders : demyelinating Charcot-Marie-Tooth (CMT) neuropathies (MTMR2 and MTMR13) and congenital myotubular/centronuclear myopathy (MTM1). These rare diseases are characterized by early onset (childhood or neonatal) and by abnormal myelination of axons or disorganization of the skeletal muscle fibers, respectively. MTM1 and MTMR2 are phosphoinositides phosphatases that specifically dephosphorylate two phosphoinositides (PtdIns3P and PtdIns(3,5)P2) known to regulate membrane trafficking in yeast and cultured cells. Moreover, the fact that the large GTPase dynamin 2, also implicated in membrane trafficking, is mutated in dominant forms of both centronuclear myopathy and CMT neuropathy, suggests a common molecular mechanism. Two partners have previously validated MTM1 and MTMR2 mouse models that reproduce the histological alterations. While the biochemical characterization of myotubularins is very competitive, the pathological mechanisms of the myotubularin-related diseases are still not well understood. We aim to study the myotubularins pathway and the specific functions of the ubiquitously expressed MTM1 and MTMR2 proteins, respectively in skeletal muscle and Schwann cells. The three partners gathered to bring the necessary expertises on phosphoinositides metabolism, and muscle and myelination pathology. We propose :
-to study the impact of myotubularins on membrane trafficking in C. elegans models, and to identify common and specific interactors, with an emphasis on tissue-specific interactors.
-to assess the role of MTMR2 in membrane trafficking in Schwann cells, both in Schwann cell/neuron co-cultures and in mice, the later point by disrupting the interaction between MTMR2 and its only known protein partner in these cells, Dlg1.
-to characterize the role of MTM1 in phosphoinositides metabolism and membrane trafficking in skeletal muscle.
This program should allow a better comprehension of the mechanisms underlying normal muscle maturation and myelination processes and their dysregulation in disease, and will bring new markers and potentially new proteins implicated in these rare neuromuscular disorders.

E-Rare 2012 - Created by Toussaint Biger