title: Dysferlin mediates membrane tubulation and links T-tubule biogenesis to muscular dystrophy.
abstract: The multi-C2 domain protein dysferlin localizes to the plasma membrane and the T-tubule system in skeletal muscle; however, its physiological mode of action is unknown. Mutations in theDYSFgene lead to autosomal recessive limb-girdle muscular dystrophy type 2B and Miyoshi myopathy. Here, we show that dysferlin has membrane tubulating capacity and that it shapes the T-tubule system. Dysferlin tubulates liposomes, generates a T-tubule-like membrane system in non-muscle cells, and links the recruitment of phosphatidylinositol 4,5-bisphosphate to the biogenesis of the T-tubule system. Pathogenic mutant forms interfere with all of these functions, indicating that muscular wasting and dystrophy are caused by the dysferlin mutants' inability to form a functional T-tubule membrane system.
authors.affiliation: Department of Child and Adolescent Health, University Medical Centre Göttingen, Göttingen 37075, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Hofhuis
authors.affiliation: Department of Child and Adolescent Health, University Medical Centre Göttingen, Göttingen 37075, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Bersch
authors.affiliation: Department of Child and Adolescent Health, University Medical Centre Göttingen, Göttingen 37075, Germany.
authors.forename: Ronja
authors.initials: R
authors.lastname: Büssenschütt
authors.affiliation: Department of Child and Adolescent Health, University Medical Centre Göttingen, Göttingen 37075, Germany.
authors.forename: Marzena
authors.initials: M
authors.lastname: Drzymalski
authors.affiliation: Department of Clinical Neurophysiology, University Medical Centre Göttingen, Göttingen 37075, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Liebetanz
authors.affiliation: Department of Cardiology and Pneumology, Heart Research Centre Göttingen, Göttingen 37075, Germany.
authors.forename: Viacheslav O
authors.initials: VO
authors.lastname: Nikolaev
authors.affiliation: Department of Internal Medicine II, University Medical Centre Regensburg, Regensburg 93042, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Wagner
authors.affiliation: Department of Internal Medicine II, University Medical Centre Regensburg, Regensburg 93042, Germany.
authors.forename: Lars S
authors.initials: LS
authors.lastname: Maier
authors.affiliation: Department of Child and Adolescent Health, University Medical Centre Göttingen, Göttingen 37075, Germany.
authors.forename: Jutta
authors.initials: J
authors.lastname: Gärtner
authors.affiliation: Department of Child and Adolescent Health, University Medical Centre Göttingen, Göttingen 37075, Germany lars.klinge@posteo.de sven.thoms@med.uni-goettingen.de.
authors.forename: Lars
authors.initials: L
authors.lastname: Klinge
authors.affiliation: Department of Child and Adolescent Health, University Medical Centre Göttingen, Göttingen 37075, Germany lars.klinge@posteo.de sven.thoms@med.uni-goettingen.de.
authors.forename: Sven
authors.identifier: 0000-0003-3018-6363
authors.initials: S
authors.lastname: Thoms
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002118:Calcium / Q000378:metabolism; D051244:Caveolin 3 / Q000378:metabolism; D002522:Chlorocebus aethiops; D034281:Dynamins / Q000378:metabolism; D000073939:Dysferlin; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000172:deficiency / Q000378:metabolism*; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000172:deficiency / Q000378:metabolism*; D009136:Muscular Dystrophies / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010641:Phenotype; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D010805:Physical Conditioning, Animal; D011485:Protein Binding; D012508:Sarcolemma / Q000378:metabolism* / Q000648:ultrastructure; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C109221:Bin1 protein, mouse; D051244:Caveolin 3; C114839:DYSF protein, human; C497505:Dysf protein, mouse; D000073939:Dysferlin; D008565:Membrane Proteins; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins; D019269:Phosphatidylinositol 4,5-Diphosphate; D025521:Tumor Suppressor Proteins; D034281:Dynamins; D002118:Calcium
keywords: 5-bisphosphate; C2 domain protein; Dysferlin; Dysferlinopathy; Limb-girdle muscular dystrophy type 2B; Miyoshi myopathy; Muscular dystrophy; Phosphatidylinositol 4; T-tubule system