Centronuclear Myopathy Caused by Defective Membrane Remodelling of Dynamin 2 and BIN1 Variants

Abstract

Centronuclear myopathy (CNM) is a congenital myopathy characterised by centralised nuclei in skeletal myofibers. T-tubules, sarcolemmal invaginations required for excitation-contraction coupling, are disorganised in the skeletal muscles of CNM patients. Previous studies showed that various endocytic proteins are involved in T-tubule biogenesis and their dysfunction is tightly associated with CNM pathogenesis. DNM2 and BIN1 are two causative genes for CNM that encode essential membrane remodelling proteins in endocytosis, dynamin 2 and BIN1, respectively. In this review, we overview the functions of dynamin 2 and BIN1 in T-tubule biogenesis and discuss how their dysfunction in membrane remodelling leads to CNM pathogenesis.

Keywords: BIN1; T-tubules; centronuclear myopathy; dynamin; membrane remodelling.

Figure 1

Functions of MTM1, BIN1 and DNM2 in T-tubule biogenesis. CNM causative genes MTM1, BIN1 and DNM2 contribute to T-tubule biogenesis in a common pathway by respectively regulating lipid homeostasis, membrane deformation and T-tubule stabilisation.

Figure 2

Domain structures of dynamin 2 and BIN1. Schematic illustrations of domain structures and CNM-associated mutations in dynamin 2 and BIN1.

Figure 3

Possible mechanisms of defective T-tubule formation caused by CNM-associated dynamin 2 mutant. CNM-associated dynamin 2 exhibits gain-of-function features with elevated GTPase and membrane fission activities compared to normal dynamin 2.

Figure 4

Determining pathogenicity of novel CNM variants by various analyses. Possible phenotypic summary of unknown variants identified from CNM patients analysed by various assays either in vitro (GTPase activity) or in cellulo (DNM2 aggregation and TLS formation) to determine their pathogenicity. N: nuclei.

Figure 5

Multiple functions of dynamin 2 in skeletal muscle cells. Dynamin 2 (blue) is involved in multiple processes in muscle cells such as T-tubule biogenesis, NMJ formation, costamere formation, endocytosis and vesicle trafficking, autophagy and lipid homeostasis.