Mutations in amphiphysin 2 (BIN1) disrupt interaction with dynamin 2 and cause autosomal recessive centronuclear myopathy.
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.
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Department of Molecular Pathology, F-67400 Illkirch, France.
Anne-Sophie
AS
Nicot
Anne
A
Toussaint
Valérie
V
Tosch
Christine
C
Kretz
Carina
C
Wallgren-Pettersson
Erik
E
Iwarsson
Helen
H
Kingston
Jean-Marie
JM
Garnier
Valérie
V
Biancalana
Anders
A
Oldfors
Jean-Louis
JL
Mandel
Jocelyn
J
Laporte
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D019556:COS Cells; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D034285:Dynamin II / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005808:Genes, Recessive; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006239:Haplotypes; D006801:Humans; D008297:Male; D051379:Mice; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D009135:Muscular Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D017386:Sequence Homology, Amino Acid; D014162:Transfection
D009419:Nerve Tissue Proteins; D049452:Green Fluorescent Proteins; C075637:amphiphysin; D034285:Dynamin II