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.
Nicot
Anne-Sophie
AS
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Department of Molecular Pathology, F-67400 Illkirch, France.
Toussaint
Anne
A
Tosch
Valérie
V
Kretz
Christine
C
Wallgren-Pettersson
Carina
C
Iwarsson
Erik
E
Kingston
Helen
H
Garnier
Jean-Marie
JM
Biancalana
Valérie
V
Oldfors
Anders
A
Mandel
Jean-Louis
JL
Laporte
Jocelyn
J
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