Résumé :
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Dynamin 2 (DNM2) mutations have been associated with two distinct clinical presentations: autosomal dominant centronuclear myopathy (CNM), a congenital myopathy, and dominant intermediate and axonal Charcot-Marie-Tooth disease (CMT), a peripheral neuropathy. To date, the sequencing of DNM2 gene has lead us to identify 13 heterozygous mutations in 39 CNM families and one mutation in an axonal CMT patient. Five DNM2-CNM mutations are located in the middle domain (MD), seven in the Pleckstrin Homology (PH) domain and one in the GTPase effector domain (GED) of the protein. The CMT-DNM2 mutation (p.K559del) is located in the PH domain in which five DNM2 mutations have been previously identified. Therefore, mutations in the PH domain cause both CNM and CMT. PH domains are classically involved in targeting proteins to the plasma membrane. Structural studies of this domain from other proteins suggest that the ?-sheets in the N-terminal part of the domain are involved in the interaction with membrane phosphoinositides and that the C-terminal part includes an ?-helix involved in protein-protein interactions. Four out of the seven CNM-mutations in this domain, affecting residues 618, 619 and 625 in the ?-helix, cause severe neonatal CNM. The 6 CMT-DNM2 mutations are restricted to a region from position 537 to 570 that includes the ?-sheet region. Only one CNM-DNM2 mutation (p.E560K) was located in this ‘CMT region’ and is associated with an atypical presentation of CNM. This CNM mutation p.E560K is associated with the muscle morphological features of CNM, which are absent in the CMT patient with the p.K559del mutation. These data enlarge the spectrum of DNM2 mutations in CNM and CMT and highlight the clinical and morphological heterogeneity associated with DNM2 mutations. The severity of the clinical phenotype associated with ?-helix PH domain CNM mutations suggests that this region is particularly important for DNM2 function in muscle.
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