Acta Neuropathologica

, Volume 121, Issue 2, pp 253–266 | Cite as

Defects in amphiphysin 2 (BIN1) and triads in several forms of centronuclear myopathies

  • Anne Toussaint
  • Belinda Simone Cowling
  • Karim Hnia
  • Michel Mohr
  • Anders Oldfors
  • Yannick Schwab
  • Uluc Yis
  • Thierry Maisonobe
  • Tanya Stojkovic
  • Carina Wallgren-Pettersson
  • Vincent Laugel
  • Andoni Echaniz-Laguna
  • Jean-Louis Mandel
  • Ichizo Nishino
  • Jocelyn LaporteEmail author
Original Paper


Myotubular myopathy and centronuclear myopathies (CNM) are congenital myopathies characterized by generalized muscle weakness and mislocalization of muscle fiber nuclei. Genetically distinct forms exist, and mutations in BIN1 were recently identified in autosomal recessive cases (ARCNM). Amphiphysins have been implicated in membrane remodeling in brain and skeletal muscle. Our objective was to decipher the pathogenetic mechanisms underlying different forms of CNM, with a focus on ARCNM cases. In this study, we compare the histopathological features from patients with X-linked, autosomal recessive, and dominant forms, respectively, mutated in myotubularin (MTM1), amphiphysin 2 (BIN1), and dynamin 2 (DNM2). We further characterize the ultrastructural defects in ARCNM muscles. We demonstrate that the two BIN1 isoforms expressed in skeletal muscle possess the phosphoinositide-binding domain and are specifically targeted to the triads close to the DHPR–RYR1 complex. Cardiac isoforms do not contain this domain, suggesting that splicing of BIN1 regulates its specific function in skeletal muscle. Immunofluorescence analyses of muscles from patients with BIN1 mutations reveal aberrations of BIN1 localization and triad organization. These defects are also observed in X-linked and autosomal dominant forms of CNM and in Mtm1 knockout mice. In addition to previously reported implications of BIN1 in cancer as a tumor suppressor, these findings sustain an important role for BIN1 skeletal muscle isoforms in membrane remodeling and organization of the excitation–contraction machinery. We propose that aberrant BIN1 localization and defects in triad structure are part of a common pathogenetic mechanism shared between the three forms of centronuclear myopathies.


Congenital myopathy Centronuclear myopathy Myotubular myopathy Amphiphysin Myotubularin Dynamin Triad T-tubule 



Autosomal dominant centronuclear myopathy


Autosomal recessive centronuclear myopathy




Centronuclear myopathy




Nicotinamide adenine dinucleotide tetrazolium reductase


Online mendelian inheritance in man




Sarcoplasmic reticulum


X-linked myotubular myopathy



We thank Christine Kretz and the IGBMC imaging center for technical assistance. This work was supported by grants from Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), University of Strasbourg, Collège de France, Association Française contre les Myopathies (AFM), Fondation Recherche Médicale (FRM DEQ20071210538), Agence Nationale de la Recherche (ANR-06-MRAR 023, ANR-07-BLAN-0065-03, ANR-08-GENOPAT-005), and the E-rare program.


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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Anne Toussaint
    • 1
    • 2
    • 3
    • 4
    • 5
  • Belinda Simone Cowling
    • 1
    • 2
    • 3
    • 4
    • 5
  • Karim Hnia
    • 1
    • 2
    • 3
    • 4
    • 5
  • Michel Mohr
    • 6
  • Anders Oldfors
    • 7
  • Yannick Schwab
    • 2
    • 3
    • 8
  • Uluc Yis
    • 9
  • Thierry Maisonobe
    • 10
    • 11
  • Tanya Stojkovic
    • 12
    • 13
  • Carina Wallgren-Pettersson
    • 14
    • 15
  • Vincent Laugel
    • 16
  • Andoni Echaniz-Laguna
    • 17
  • Jean-Louis Mandel
    • 1
    • 2
    • 3
    • 4
    • 5
  • Ichizo Nishino
    • 18
  • Jocelyn Laporte
    • 1
    • 2
    • 3
    • 4
    • 5
    Email author
  1. 1.Department of Neurobiology and GeneticsInstitut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)IllkirchFrance
  2. 2.INSERM, U964IllkirchFrance
  3. 3.CNRS, UMR7104IllkirchFrance
  4. 4.Université de StrasbourgIllkirchFrance
  5. 5.Chaire de Génétique HumaineCollège de FranceIllkirchFrance
  6. 6.Service d’Anatomie PathologiqueCentre Hospitalier Universitaire (CHU) HautepierreStrasbourgFrance
  7. 7.Department of Pathology, Institute of BiomedicineUniversity of GothenburgGothenburgSweden
  8. 8.Imaging PlatformInstitut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)IllkirchFrance
  9. 9.Division of Child NeurologyGaziantep Children’s HospitalGaziantepTurkey
  10. 10.Service de NeuropathologieGroupe Hospitalier Pitié-Salpêtrière, AP-HPParisFrance
  11. 11.Fédération de Neurophysiologie CliniqueGroupe Hospitalier Pitié-Salpêtrière, AP-HPParisFrance
  12. 12.Unité de Morphologie Neuromusculaire, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, AP-HPParisFrance
  13. 13.Centre de Référence Neuromusculaire Paris-EstInstitut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, AP-HPParisFrance
  14. 14.Department Medical Genetics, The Haartman InstituteUniversity of HelsinkiHelsinkiFinland
  15. 15.The Folkhälsan Institute of GeneticsHelsinkiFinland
  16. 16.Service de PédiatrieCentre Hospitalier Universitaire (CHU) HautepierreStrasbourgFrance
  17. 17.Department of NeurologyHôpital CivilStrasbourgFrance
  18. 18.Department of Neuromuscular ResearchNational Institute of Neuroscience, National Center of Neurology and PsychiatryKodairaJapan

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