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Mécanismes Pathologiques Des Myopathies Centronucléaires Autosomales Récessives

出版	2013
URL	http://books.google.com.hk/books?id=AJAk0AEACAAJ&hl=&source=gbs_api

註釋BIN1 is a membrane tubulating protein and it consists of the BAR domain which binds membranes and has tubulating property; the PI motif which binds phosphoinositides and is expressed only in skeletal muscle; the CLAP domain binds clathrin and AP2 and is present exclusively in brain isoforms of BIN1; the MBD is involved in c-Myc binding and the SH3 domain is involved in interactions with prolin-rich proteins. BIN1 is an ubiquitously expressed protein with the highest expression in skeletal muscle. Mutations in amphiphysin 2 / BIN1 were found to cause autosomal recessive centronuclear myopathy (ARCNM, OMIM 255200). Mutations in patients were found in all the protein domains and include two mutations leading to a premature stop codon in the last exon 20. The PI motive, encoded by exon 11, is upregulated during myogenesis. The aim of this research was to better understand the role of BIN1 in healthy muscle and in the pathology of CNM. For this purpose, by using targeted homologous recombination in ES cells, we generated two knockout mouse models: BIN1 exon 11 and BIN1 exon 20, with exon 11 and 20 deleted, respectively. The deletion of exon 20 disrupts the SH3 domain, involved in interactions with different proteins, amongst which is dynamin 2 and induced a considerable loss of the total BIN1 protein expression. The total and muscle specific deletions of exon 20 were perinatally lethal. A disrupted T-tubules organization was observed in knockout mice, showing an importance of BIN1 during the T-tubule biogenesis. Interestingly, deletion induced in adult mice did not affect muscle function and organization. In order to understand the role of the muscle specific PI motif, we characterized the BIN1 exon 11 KO mice. Even at 12 months of age the muscle function in mice was not compromised by this deletion. However, further examination showed impairment of skeletal muscle regeneration. This work revealed that in vivo, BIN1 is necessary during the T-tubules biogenesis and dispensable for muscle maintenance, whereas the skeletal muscle specific PI motif of BIN1 is involved in muscle regeneration. Its function in muscle is tightly regulated by isoform switch and intramolecular binding. Understanding these features will help us step forward towards successful therapy in ARCNM and MD patients.