Centronuclear myopathies (CNMs) are a group of inherited neuromuscular disorders characterized by muscle weakness, fiber atrophy, predominance of type I fibers, and increased centralization of nuclei not due to muscle regeneration [for review, see Jungbluth et al. (2008)].
CNMs are genetically widely heterogeneous, and three classical forms of CNM have been characterized:
- X-linked CNM (XLCNM; OMIM 310400), due to mutations in the phosphoinositides phosphatase myotubularin (MTM1) (Laporte et al., 1996);
- Autosomal recessive CNM (ARCNM, OMIM 255200), caused by mutations in the membrane remodeling protein amphiphysin 2 (BIN1) (Bohm et al., 2014);
- Autosomal dominant CNM (ADCNM, OMIM 160150), due to mutations in dynamin 2 (DNM2) (Bitoun et al., 2005).
Mutations in other genes have also been indicated in Centronuclear myopathies, including titin (TTN, Ceyan-Birsoy et al, 2013) and Ryanodine receptor (RYR1, Bevilacqua et al 2001, Wilmshurst et al 2010).
The relationship between the implicated genes in muscle is not well known. However, Jocelyn Laporte and Belinda Cowling, cofounders of Dynacure, demonstrated that dynamin 2 is overexpressed in X-linked CNM. They have also demonstrated that overexpression of dynamin 2 in wild-type mice induces a CNM-like phenotype (Cowling et al., 2011). Subsequently, it was shown that the reduction of dynamin 2 to 50% by genetic cross leads to mice without MTM1 that do not have the disease; i.e., prevention of the phenotype in a relevant XLCNM mouse model (Cowling et al. 2014). The next step is to develop a translated approach that can be used to regulate dynamin 2 in patients.