The dysferlin protein is a roughly 220 kilodalton type-II transmembrane protein. It contains a large intracellular cytoplasmic N-terminal domain, an extreme C-terminal transmembrane domain, and a short C-terminal extracellular domain. The cytosolic domain of dysferlin is composed of 6 highly conserved C2 domains (C2A-F) which are conserved across several proteins within the ferlin family, including dysferlin homolog myoferlin. In fact, the C2 domain at any given position is more similar to the C2 domain at the corresponding position within other ferlin family members than the adjacent C2 domain within the same protein. This suggests that each individual C2 domain may in fact play a specific role in dysferlin function. A crystal structure of the C2A domain of dysferlin has been solved, and reveals that the C2A domain changes conformation when interacting with calcium ions, which is consistent with a growing body of evidence suggesting that the C2A domain plays a role in calcium-dependent lipid binding. In addition to the C2 domains, dysferlin also contains "Fer" and "Dysf" domains of largely unknown function.
The most intensively studied role for dysferlin is in a cellular process called membrane repair. Membrane repair is a critical mechanism by which cells are able to seal dramatic wounds to the plasma membrane. Muscle is thought to be particularly prone to membrane wounds given that muscle cells transmit high force and undergo cycles of contraction. Dysferlin is highly expressed in muscle, and is homologous to the ferlin family of proteins, which are thought to regulate membrane fusion across a wide variety of species and cell types. Several lines of evidence suggest that dysferlin may be involved in membrane repair in muscle. First, dysferlin-deficient muscle fibers show accumulation of vesicles (which are critical for membrane repair in non-muscle cell types) near membrane lesions, indicating that dysferlin may be required for fusion of repair vesicles with the plasma membrane. Further, dysferlin-deficient muscle fibers take up extracellular dyes to a greater extent than wild-type muscle fibers following laser-induced wounding in-vitro. Dysferlin is also markedly enriched at membrane lesions with several additional proteins thought to be involved in membrane resealing, including annexin and MG53. Exactly how dysferlin contributes to membrane resealing is not clear, but biochemical evidence indicates that dysferlin may bind lipids in a calcium-dependent manner, consistent with a role for dysferlin in regulating fusion of repair vesicles with the sarcolemma during membrane repair. Furthermore, live-cell imaging of dysferlin-eGFP expressing myotubes indicates that dysferlin localizes to a cellular compartment that responds to injury by forming large dysferlin-containing vesicles, and formation of these vesicles may contribute to wound repair.
Dysferlin has been shown to interact with Caveolin 3 in skeletal muscle., and this interaction is thought to retain dysferlin within the plasma membrane. Dysferlin also interacts with MG53, and a functional interaction between dysferlin, caveolin-3 and MG53 is thought to be critical for membrane repair in skeletal muscle.
^Vafiadaki E, Reis A, Keers S, Harrison R, Anderson LV, Raffelsberger T et al. (2001). "Cloning of the mouse dysferlin gene and genomic characterization of the SJL-Dysf mutation". Neuroreport12 (3): 625–9. doi:10.1097/00001756-200103050-00039. PMID11234777.
^Fuson K, Rice A, Mahling R, Snow A, Nayak K, Shanbhogue P et al. (2014). "Alternate splicing of dysferlin C2A confers Ca²⁺-dependent and Ca²⁺-independent binding for membrane repair". Structure22 (1): 104–15. doi:10.1016/j.str.2013.10.001. PMID24239457.
^Therrien C, Di Fulvio S, Pickles S, Sinnreich M (2009). "Characterization of lipid binding specificities of dysferlin C2 domains reveals novel interactions with phosphoinositides". Biochemistry48 (11): 2377–84. doi:10.1021/bi802242r. PMID19253956.
^Bashir R, Britton S, Strachan T, Keers S, Vafiadaki E, Lako M et al. (1998). "A gene related to Caenorhabditis elegans spermatogenesis factor fer-1 is mutated in limb-girdle muscular dystrophy type 2B". Nat. Genet.20 (1): 37–42. doi:10.1038/1689. PMID9731527.
^Bansal D, Miyake K, Vogel SS, Groh S, Chen CC, Williamson R et al. (2003). "Defective membrane repair in dysferlin-deficient muscular dystrophy". Nature423 (6936): 168–72. doi:10.1038/nature01573. PMID12736685.
^Abdullah N, Padmanarayana M, Marty NJ, Johnson CP (2014). "Quantitation of the calcium and membrane binding properties of the C2 domains of dysferlin". Biophys. J.106 (2): 382–9. doi:10.1016/j.bpj.2013.11.4492. PMID24461013.
^McDade JR, Michele DE (2014). "Membrane damage-induced vesicle-vesicle fusion of dysferlin-containing vesicles in muscle cells requires microtubules and kinesin". Hum. Mol. Genet.23 (7): 1677–86. doi:10.1093/hmg/ddt557. PMID24203699.
^Matsuda C, Hayashi YK, Ogawa M, Aoki M, Murayama K, Nishino I et al. (August 2001). "The sarcolemmal proteins dysferlin and caveolin-3 interact in skeletal muscle". Hum. Mol. Genet.10 (17): 1761–6. doi:10.1093/hmg/10.17.1761. PMID11532985.
^Hernández-Deviez DJ, Howes MT, Laval SH, Bushby K, Hancock JF, Parton RG (2008). "Caveolin regulates endocytosis of the muscle repair protein, dysferlin". J. Biol. Chem.283 (10): 6476–88. doi:10.1074/jbc.M708776200. PMID18096699.
Bejaoui K, Hirabayashi K, Hentati F, Haines JL, Ben Hamida C, Belal S et al. (1995). "Linkage of Miyoshi myopathy (distal autosomal recessive muscular dystrophy) locus to chromosome 2p12-14". Neurology45 (4): 768–72. doi:10.1212/wnl.45.4.768. PMID7723968.
Bashir R, Strachan T, Keers S, Stephenson A, Mahjneh I, Marconi G et al. (1994). "A gene for autosomal recessive limb-girdle muscular dystrophy maps to chromosome 2p". Hum. Mol. Genet.3 (3): 455–7. doi:10.1093/hmg/3.3.455. PMID8012357.
Liu J, Aoki M, Illa I, Wu C, Fardeau M, Angelini C et al. (1998). "Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy". Nat. Genet.20 (1): 31–6. doi:10.1038/1682. PMID9731526.
Bashir R, Britton S, Strachan T, Keers S, Vafiadaki E, Lako M et al. (1998). "A gene related to Caenorhabditis elegans spermatogenesis factor fer-1 is mutated in limb-girdle muscular dystrophy type 2B". Nat. Genet.20 (1): 37–42. doi:10.1038/1689. PMID9731527.
Anderson LV, Davison K, Moss JA, Young C, Cullen MJ, Walsh J et al. (1999). "Dysferlin is a plasma membrane protein and is expressed early in human development". Hum. Mol. Genet.8 (5): 855–61. doi:10.1093/hmg/8.5.855. PMID10196375.
Weiler T, Bashir R, Anderson LV, Davison K, Moss JA, Britton S et al. (1999). "Identical mutation in patients with limb girdle muscular dystrophy type 2B or Miyoshi myopathy suggests a role for modifier gene(s)". Hum. Mol. Genet.8 (5): 871–7. doi:10.1093/hmg/8.5.871. PMID10196377.
Matsuda C, Aoki M, Hayashi YK, Ho MF, Arahata K, Brown RH (1999). "Dysferlin is a surface membrane-associated protein that is absent in Miyoshi myopathy". Neurology53 (5): 1119–22. doi:10.1212/wnl.53.5.1119. PMID10496277.
Aoki M, Liu J, Richard I, Bashir R, Britton S, Keers SM et al. (2001). "Genomic organization of the dysferlin gene and novel mutations in Miyoshi myopathy". Neurology57 (2): 271–8. doi:10.1212/wnl.57.2.271. PMID11468312.
Matsuda C, Hayashi YK, Ogawa M, Aoki M, Murayama K, Nishino I et al. (2001). "The sarcolemmal proteins dysferlin and caveolin-3 interact in skeletal muscle". Hum. Mol. Genet.10 (17): 1761–6. doi:10.1093/hmg/10.17.1761. PMID11532985.
Ikezoe K, Furuya H, Ohyagi Y, Osoegawa M, Nishino I, Nonaka I et al. (2003). "Dysferlin expression in tubular aggregates: their possible relationship to endoplasmic reticulum stress". Acta Neuropathol.105 (6): 603–9. doi:10.1007/s00401-003-0686-1. PMID12664320.
von Tell D, Bruder CE, Anderson LV, Anvret M, Ahlberg G (2003). "Refined mapping of the Welander distal myopathy region on chromosome 2p13 positions the new candidate region telomeric of the DYSF locus". Neurogenetics4 (4): 173–7. doi:10.1007/s10048-003-0154-z. PMID12836053.
Lennon NJ, Kho A, Bacskai BJ, Perlmutter SL, Hyman BT, Brown RH (2003). "Dysferlin interacts with annexins A1 and A2 and mediates sarcolemmal wound-healing". J. Biol. Chem.278 (50): 50466–73. doi:10.1074/jbc.M307247200. PMID14506282.
Katz JS, Rando TA, Barohn RJ, Saperstein DS, Jackson CE, Wicklund M et al. (2003). "Late-onset distal muscular dystrophy affecting the posterior calves". Muscle Nerve28 (4): 443–8. doi:10.1002/mus.10458. PMID14506716.
Confalonieri P, Oliva L, Andreetta F, Lorenzoni R, Dassi P, Mariani E et al. (2003). "Muscle inflammation and MHC class I up-regulation in muscular dystrophy with lack of dysferlin: an immunopathological study". J. Neuroimmunol.142 (1-2): 130–6. doi:10.1016/S0165-5728(03)00255-8. PMID14512171.
Cagliani R, Fortunato F, Giorda R, Rodolico C, Bonaglia MC, Sironi M et al. (2003). "Molecular analysis of LGMD-2B and MM patients: identification of novel DYSF mutations and possible founder effect in the Italian population". Neuromuscul. Disord.13 (10): 788–95. doi:10.1016/S0960-8966(03)00133-0. PMID14678801.
Capanni C, Sabatelli P, Mattioli E, Ognibene A, Columbaro M, Lattanzi G et al. (2003). "Dysferlin in a hyperCKaemic patient with caveolin 3 mutation and in C2C12 cells after p38 MAP kinase inhibition". Exp. Mol. Med.35 (6): 538–44. doi:10.1038/emm.2003.70. PMID14749532.
Brüss M, Homann J, Molderings GJ (2004). "[Dysferlinopathy as an extrahepatic cause for the elevation of serum transaminases]". Med. Klin. (Munich)99 (6): 326–9. doi:10.1007/s00063-004-1046-1. PMID15221058.
The Jain Foundation is focused on finding a cure for dysferlin deficiency. The foundation is sponsoring targeted research and helping to educate patients on the importance of determining the mutations they carry in their dysferlin gene.