BIN1 modulation in vivo rescues dynamin-related myopathy

Proc Natl Acad Sci U S A. 2022 Mar 1;119(9):e2109576119. doi: 10.1073/pnas.2109576119.


The mechanoenzyme dynamin 2 (DNM2) is crucial for intracellular organization and trafficking. DNM2 is mutated in dominant centronuclear myopathy (DNM2-CNM), a muscle disease characterized by defects in organelle positioning in myofibers. It remains unclear how the in vivo functions of DNM2 are regulated in muscle. Moreover, there is no therapy for DNM2-CNM to date. Here, we overexpressed human amphiphysin 2 (BIN1), a membrane remodeling protein mutated in other CNM forms, in Dnm2RW/+ and Dnm2RW/RW mice modeling mild and severe DNM2-CNM, through transgenesis or with adeno-associated virus (AAV). Increasing BIN1 improved muscle atrophy and main histopathological features of Dnm2RW/+ mice and rescued the perinatal lethality and survival of Dnm2RW/RW mice. In vitro experiments showed that BIN1 binds and recruits DNM2 to membrane tubules, and that the BIN1-DNM2 complex regulates tubules fission. Overall, BIN1 is a potential therapeutic target for dominant centronuclear myopathy linked to DNM2 mutations.

Keywords: amphiphysin; congenital myopathy; dynamin; gene therapy; membrane remodeling.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Dynamin II / genetics
  • Dynamin II / metabolism
  • Dynamin II / physiology*
  • Humans
  • Mice
  • Mice, Knockout
  • Muscular Atrophy / physiopathology*
  • Muscular Diseases / pathology*
  • Nuclear Proteins / metabolism*
  • Protein Binding
  • Tumor Suppressor Proteins / metabolism*


  • Adaptor Proteins, Signal Transducing
  • BIN1 protein, human
  • Nuclear Proteins
  • Tumor Suppressor Proteins
  • DNM2 protein, human
  • Dynamin II