The autosomal dominant Centronuclear myopathy (CNM) is a rare form of congenital myopathy characterized by abnormal centrally located nuclei in a large proportion of muscle fibers. No curative treatment is currently available and the pathophysiological processes are largely unknown. Our group has identified the first mutations responsible for the disease in the DNM2 gene encoding the dynamin 2 (DNM2) (Bitoun et al, 2005). The objectives of our group are devoted to:

The DNM2-CNM is characterized by delayed motor milestones and slowly progressive muscular weakness and wasting. Nevertheless, there is a wide clinical spectrum from severe neonatal to milder adult forms with a marked variability in the degree of weakness. The most frequent histological features in muscle biopsies from DNM2-CNM patients consist of nuclear centralisation associated with atrophy and predominance of type 1 fibres and radial arrangement of sarcoplasmic strands radiating from the central nuclei. During the last years, our group, in collaboration with the clinicians of the Institute and the morphology unit of NB Romero, has significantly contributed to enlarge the spectrum of DNM2 mutations and their clinical and histopathological characterization (Bitoun et al, 2009a; Bitoun et al, 2007; Fischer et al, 2006; Jeub et al, 2008) as well as the characterization of the other forms of CNM without DNM2 mutations (Bevilacqua et al, 2009; Claeys et al, 2010).

DNM2 is a large GTPase, ubiquitously expressed, initially involved in membrane trafficking where the protein act as a mechanochemical scaffolding molecule that can hydrolyze GTP to deform biological membranes leading to the release of nascent vesicles. At the plasma membrane, DNM2 is involved in the clathrin- or caveolin-dependent endocytosis as well as in the clathrin- and caveolin-independent processes (Durieux et al, 2010). DNM2 is also involved in the intracellular membrane trafficking by mediating formation of vesicles from endosomes and trans-Golgi network. Several studies have also highlighted the interaction of the DNM2 with both actin and microtubule cytoskeletons (Durieux et al, 2010). DNM2 is a component of the centrosome, the main microtubules organizing center, and we showed a defect of centrosome targeting for transfected DNM2 mutants in fibroblasts suggesting a centrosome dysfunction as pathophysiological mechanism (Bitoun et al, 2005). More recently, we showed that expression of DNM2 mutants in COS7 cells leads to an impairment of clathrin-mediated receptor endocytosis (Bitoun et al, 2009b). To better understand the pathophysiological mechanisms in vivo, we recently developed the first transgenic DNM2 mouse model, i.e. a Knock-In model expressing the more frequent DNM2-CNM mutation. The characterization of the muscular phenotype in this model is in progress. This model will be useful to determine the pathomechanisms associated to DNM2 dysfunction as well as to identify the functions played by the DNM2 in the muscle fibers, especially in the membrane trafficking processes which are still largely unknown.