Mutations in amphiphysin 2 (BIN1) disrupt interaction with dynamin 2 and cause autosomal recessive centronuclear myopathy

Nat Genet. 2007 Sep;39(9):1134-9. doi: 10.1038/ng2086. Epub 2007 Aug 5.


Centronuclear myopathies are characterized by muscle weakness and abnormal centralization of nuclei in muscle fibers not secondary to regeneration. The severe neonatal X-linked form (myotubular myopathy) is due to mutations in the phosphoinositide phosphatase myotubularin (MTM1), whereas mutations in dynamin 2 (DNM2) have been found in some autosomal dominant cases. By direct sequencing of functional candidate genes, we identified homozygous mutations in amphiphysin 2 (BIN1) in three families with autosomal recessive inheritance. Two missense mutations affecting the BAR (Bin1/amphiphysin/RVS167) domain disrupt its membrane tubulation properties in transfected cells, and a partial truncation of the C-terminal SH3 domain abrogates the interaction with DNM2 and its recruitment to the membrane tubules. Our results suggest that mutations in BIN1 cause centronuclear myopathy by interfering with remodeling of T tubules and/or endocytic membranes, and that the functional interaction between BIN1 and DNM2 is necessary for normal muscle function and positioning of nuclei.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Binding Sites / genetics
  • COS Cells
  • Cell Line
  • Cell Nucleus / metabolism
  • Chlorocebus aethiops
  • Dynamin II / genetics*
  • Dynamin II / metabolism
  • Female
  • Genes, Recessive
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Haplotypes
  • Humans
  • Male
  • Mice
  • Microscopy, Confocal
  • Molecular Sequence Data
  • Muscular Diseases / genetics*
  • Muscular Diseases / metabolism
  • Muscular Diseases / pathology
  • Mutation*
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Polymorphism, Single Nucleotide
  • Protein Binding
  • Sequence Homology, Amino Acid
  • Transfection


  • Nerve Tissue Proteins
  • Green Fluorescent Proteins
  • amphiphysin
  • Dynamin II

Associated data

  • PDB/1BB9
  • RefSeq/NM_004305
  • RefSeq/NM_139343
  • RefSeq/NP_004296
  • RefSeq/NP_647593
  • SWISSPROT/P25343
  • SWISSPROT/P39743
  • SWISSPROT/P49418
  • SWISSPROT/P53365
  • SWISSPROT/Q21004
  • SWISSPROT/Q99962