Abstract
Centronuclear myopathies (CNM) are rare congenital disorders characterized by muscle weakness and structural defects including fiber hypotrophy and organelle mispositioning. The main CNM forms are caused by mutations in: the MTM1 gene encoding the phosphoinositide phosphatase myotubularin (myotubular myopathy), the DNM2 gene encoding the mechanoenzyme dynamin 2, the BIN1 gene encoding the membrane curvature sensing amphiphysin 2, and the RYR1 gene encoding the skeletal muscle calcium release channel/ryanodine receptor. MTM1, BIN1, and DNM2 proteins are involved in membrane remodeling and trafficking, while RyR1 directly regulates excitation-contraction coupling (ECC). Several CNM animal models have been generated or identified, which confirm shared pathological anomalies in T-tubule remodeling, ECC, organelle mispositioning, protein homeostasis, neuromuscular junction, and muscle regeneration. Dynamin 2 plays a crucial role in CNM physiopathology and has been validated as a common therapeutic target for three CNM forms. Indeed, the promising results in preclinical models set up the basis for ongoing clinical trials. Another two clinical trials to treat myotubular myopathy by MTM1 gene therapy or tamoxifen repurposing are also ongoing. Here, we review the contribution of the different CNM models to understanding physiopathology and therapy development with a focus on the commonly dysregulated pathways and current therapeutic targets.
Highlights
Centronuclear myopathies (CNM) are a subgroup of congenital muscle disorders encompassing myotubular myopathy and are characterized by the abnormal nuclei position in the center of the myofibers in the absence of excessive regeneration, unlike what is commonly observed in dystrophies [1]
The first in vivo model for autosomal dominant CNM (ADCNM) was generated by homologous recombination and expresses the most frequent dynamin 2 (DNM2) mutation observed in patients (Dnm2R465W/+ ) [93]
In the last few years, several advances in the understanding of the pathomechanisms have been made, which have led to the identification of novel therapeutic strategies, some of which are in clinical trials
Summary
Centronuclear myopathies (CNM) are a subgroup of congenital muscle disorders encompassing myotubular myopathy and are characterized by the abnormal nuclei position in the center of the myofibers in the absence of excessive regeneration, unlike what is commonly observed in dystrophies [1]. Clinical presentation and inheritance are heterogenous and can be classified into three main groups: the most severe X-linked CNM (XLMTM, myotubular myopathy) caused by mutations in MTM1 encoding myotubularin (MTM1) [3]; autosomal dominant CNM (ADCNM) caused by dominant mutations in DNM2 encoding dynamin 2 (DNM2) [4] or in BIN1 encoding amphiphysin. Mutations in other genes including TTN [10], SPEG [11], CACNA1S [12], and ZAK [13] have been identified in congenital myopathies with a CNM-like phenotype combined with other features. In the present review we aim to provide an overview of the clinical and pathological aspects of CNM with a focus on the main genetic forms with mutations in MTM1, BIN1, DNM2, and RYR1 genes, and highlight common disease mechanisms. Updates on novel therapeutic targets and a current translation of different treatment approaches to human clinical trials will be discussed
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