Official websites use. Share sensitive information only on official, secure websites. Mutations in the BIN1 Bridging Interactor 1 gene, encoding the membrane remodeling protein amphiphysin 2, cause centronuclear myopathy CNM associated with severe muscle weakness and myofiber disorganization and hypotrophy. There is no available therapy, and the validation of therapeutic proof of concept is impaired by the lack of a faithful and easy-to-handle mammalian model. Keywords: myopathy, antisense oligonucleotides, membrane curvature, dynamin, amphiphysin, therapy, MTM1, myotubular myopathy, myotubularin, t-tubule.
Dnm2 downregulation in this model improves most phenotypes, offering promising perspectives for BIN1-CNM patient treatment. A plethora of muscle diseases impair different steps of muscle formation or maintenance. Centronuclear myopathies CNMs are rare genetic diseases associated with a severe generalized muscle weakness associated with myofiber hypotrophy and premature death.
Despite the significant impact on morbidity and mortality, to date there is no specific therapy available for CNM patients. Regarding the understanding and treatment of BIN1-CNM, the two main bottlenecks are the absence of a faithful and easy-to-handle mammalian model and the lack of therapeutic proof of concept necessary to trigger clinical development.
A Drosophila mutant for Amph, the BIN1 ortholog, is flightless, with severe structural defects of the triads, the structural basis of excitation-contraction coupling formed by a T-tubule contacting 2 terminal cisternae of sarcoplasmic reticulum SR.
Some potential therapies for CNMs have been proposed. However, it was never tested for BIN1-CNM due to lack of a faithful viable mouse model, albeit genetic crosses recently suggested that decreasing Dnm2 prevents the neonatal death of Bin1 knockout mice.
