Some mutations affecting dynamin 2 (DNM2) can cause dominantly inherited Charcot-Marie-Tooth (CMT) neuropathy. Here, we describe the analysis of mice carrying the DNM2 K562E mutation which has been associated with dominant-intermediate CMT type B (CMTDIB). Contrary to our expectations, heterozygous DNM2 K562E mutant mice did not develop definitive signs of an axonal or demyelinating neuropathy. Rather, we found a primary myopathy-like phenotype in these mice. A likely interpretation of these results is that the lack of a neuropathy in this mouse model has allowed the unmasking of a primary myopathy due to the DNM2 K562E mutation which might be overshadowed by the neuropathy in humans. Consequently, we hypothesize that a primary myopathy may also contribute to the disease mechanism in some CMTDIB patients. We propose that these findings should be considered in the evaluation of patients, the determination of the underlying disease processes and the development of tailored potential treatment strategies.

Mutations of Dynamin 2 (DNM2) are responsible for several forms of neuromuscular disorder such as centronuclear myopathy, Charcot-Marie-Tooth disease (CMT) dominant intermediate type B, CMT 2M, and lethal congenital contracture syndrome 5. We describe a young man manifesting as length-dependent sensorimotor neuropathy with hypertrophic cardiomyopathy, but his mother only had very mild symptoms of peripheral neuropathy. The electrophysiological data meet the criteria of intermediate CMT. The main pathological findings of sural nerve biopsy reveal a severe loss of large myelinating fibers and some clusters of regenerative fibers in fascicles, which are consistent with an axonal neuropathy. However, myopathological changes show a chronic myopathy-like pattern characterized by great variations of fiber size, increased connective tissue, rimmed vacuoles and predominance of type 2 fibers. A novel DNM2 mutation (p.G359D) in the middle domain is identified, which is highly evolutionarily conserved. DNM2-related CMT disease is phenotypically heterogeneous in age at onset, clinical features and electrophysiological changes. The histopathological findings indicate the coexistence of typical axonal neuropathy and chronic myopathy in DNM2-related neuromuscular diseases.

Mutations in the dynamin-2 gene (DNM2) cause autosomal dominant centronuclear myopathy (CNM) and dominant intermediate Charcot-Marie-Tooth (CMT) neuropathy type B (CMTDIB). As the relation between these DNM2-related diseases is poorly understood, we used zebrafish to investigate the effects of two different DNM2 mutations. First we identified a new alternatively spliced zebrafish dynamin-2a mRNA (dnm2a-v2) with greater similarity to human DNM2 than the deposited sequence. Then we knocked-down the zebrafish dnm2a, producing defects in muscle morphology. Finally, we expressed two mutated DNM2 mRNA by injecting zebrafish embryos with human mRNAs carrying the R522H mutation, causing CNM, or the G537C mutation, causing CMT. Defects arose especially in secondary motor neuron formation, with incorrect branching in embryos injected with CNM-mutated mRNA, and total absence of branching in those injected with CMT-mutated mRNA. Muscle morphology in embryos injected with CMT-mutated mRNA appeared less regularly organized than in those injected with CNM-mutated mRNA. Our results showing, a continuum between CNM and CMTDIB phenotypes in zebrafish, similarly to the human conditions, confirm this animal model to be a powerful tool to investigate mutations of DNM2 in vivo.