# DYSF

## Overview
Dysferlin is a protein encoded by the DYSF gene, which is primarily involved in the repair and maintenance of muscle cell membranes. The gene DYSF is located on chromosome 2p13 and expresses dysferlin, a type II transmembrane protein that is crucial for the cellular processes that repair muscle tissue following injury. Dysferlin is characterized by its structure containing multiple C2 domains, which are calcium-dependent lipid-binding motifs, essential for mediating interactions with phospholipid membranes during the repair process. This protein is predominantly expressed in skeletal and cardiac muscles, where it plays a pivotal role in maintaining the integrity of muscle cells, particularly under conditions of mechanical stress. Mutations in the DYSF gene are associated with several forms of muscular dystrophies, known as dysferlinopathies, which are characterized by progressive muscle weakness and degeneration (Nguyen2005Dysferlin; Cárdenas2016Dysferlin).

## Structure
Dysferlin, encoded by the DYSF gene, is a type II transmembrane protein that plays a crucial role in muscle membrane repair. The primary structure of dysferlin comprises multiple domains that are critical for its function. Notably, it contains seven C2 domains, which are calcium-binding motifs that facilitate interactions with phospholipid membranes during the repair process. Additionally, dysferlin includes other specific domains such as FerI, FerA, FerB, a double DysF internal Nter, a double DysF internal Cter, and a C-terminal transmembrane domain (TM) (Lostal2019Therapeutic).

The secondary, tertiary, and quaternary structures of dysferlin are not detailed in the available literature. However, the presence of multiple C2 domains suggests a complex arrangement allowing for versatile interactions with cellular membranes and other proteins involved in vesicle trafficking and membrane repair.

Dysferlin also exhibits several splice variant isoforms, which result from alternative splicing. These isoforms include differences in the inclusion of specific exons, such as the exclusion of exon 17 in some variants found in peripheral nerve tissue, which may affect the protein's function in tissue-specific contexts (Salani2004Developmental).

Overall, the molecular structure of dysferlin, characterized by its multiple domains and splice variants, underpins its essential role in cellular repair mechanisms and its involvement in muscular dystrophies.

## Function
Dysferlin, encoded by the DYSF gene, is a type II transmembrane protein that plays a critical role in the repair of skeletal muscle cell membranes. This protein is essential for maintaining the stability and integrity of muscle cell membranes, especially under conditions where they may be damaged by mechanical stress. Dysferlin facilitates the membrane repair process by mediating vesicle fusion at the site of membrane disruption, a process that is vital for preventing degenerative necrosis of muscle cells (Wang2024Two). The protein is predominantly expressed in skeletal and cardiac muscle tissues, where it is localized to the plasma membrane of muscle fibers and cytoplasmic vesicles (Cacciottolo2011Reverse).

Dysferlin contains multiple C2 domains that bind phospholipids in a calcium-dependent manner, which is crucial for its function in membrane repair. The protein interacts with various other proteins involved in membrane trafficking and fusion, such as caveolin-3, annexins A1 and A2, and others, which are critical for the structural integrity and functional capacity of muscle cells (Dominov2014A). Dysferlin's ability to bind and organize phospholipids at the site of cellular damage supports rapid membrane resealing, thereby preserving muscle cell function and preventing muscle fiber damage (Cacciottolo2011Reverse; Dominov2014A).

## Clinical Significance
Mutations in the DYSF gene, which encodes the dysferlin protein, are linked to a spectrum of autosomal recessive muscular dystrophies collectively known as dysferlinopathies. These include Miyoshi myopathy (MM), limb-girdle muscular dystrophy type 2B (LGMD2B), and distal anterior compartment myopathy. Dysferlinopathies are characterized by progressive muscle atrophy and weakness, typically beginning between the second and third decades of life. The clinical presentation can vary significantly, even among members of the same family, and may include symptoms such as elevated plasma creatine kinase levels, muscle weakness spreading from the lower limbs to upper body muscles, and in some cases, cardiac involvement (Vilchez2005Identification; Cárdenas2016Dysferlin).

The mutations identified in the DYSF gene range from missense and nonsense mutations to frame-shifts and intronic mutations, which can affect mRNA splicing, gene expression, and protein function. These genetic alterations lead to a reduction or absence of the dysferlin protein, crucial for membrane repair and vesicle trafficking in muscle cells, thereby contributing to muscle damage and the symptoms observed in dysferlinopathy (Nguyen2005Dysferlin; Fanin2016Progress).

Accurate diagnosis of dysferlinopathies relies on a combination of genetic testing, including Sanger sequencing, next-generation sequencing (NGS), and cDNA analysis from muscle mRNA to detect these mutations. Identifying the specific mutations in the DYSF gene not only confirms the diagnosis but also aids in genetic counseling and guides future therapeutic interventions (Fanin2016Progress).

## Interactions
Dysferlin (DYSF) interacts with a variety of proteins involved in muscle membrane repair and cellular processes. Notably, dysferlin forms direct interactions with proteins such as Trim72/MG53, AHNAK, cytoplasmic dynein, myomesin-2, and calsequestrin-1, which play significant roles in muscle physiology and pathology (Flix2013Dysferlin). Dysferlin also interacts with annexin A1 and caveolin-3, although the interaction with caveolin-3 is not direct (Flix2013Dysferlin). Additionally, dysferlin is involved in vesicular trafficking and muscle regeneration through its interactions with proteins like annexin A2, striatin, adaptin alpha, and utrophin (Assadi2008Identification).

In the context of skeletal muscle regeneration, dysferlin interacts with AHNAK, a protein that binds dysferlin through its carboxyterminal end, specifically the C2A domain of dysferlin (Huang2006AHNAK). Dysferlin also forms complexes with proteins involved in cellular pathways such as the focal adhesion pathway, interacting with vinculin, actinin, and talin, which are crucial for cell-cell and cell-matrix contacts (de2010Proteomic). These interactions underscore dysferlin's role in sarcolemmal maintenance and integrity, essential for proper muscle function and repair.


## References


[1. (Salani2004Developmental) Sabrina Salani, Sabrina Lucchiari, Francesco Fortunato, Marco Crimi, Stefania Corti, Federica Locatelli, Patrizia Bossolasco, Nereo Bresolin, and Giacomo Pietro Comi. Developmental and tissue‐specific regulation of a novel dysferlin isoform. Muscle & Nerve, 30(3):366–374, July 2004. URL: http://dx.doi.org/10.1002/mus.20106, doi:10.1002/mus.20106. (29 citations) 10.1002/mus.20106](https://doi.org/10.1002/mus.20106)

[2. (Lostal2019Therapeutic) William Lostal and Isabelle Richard. Therapeutic Approaches for Dysferlinopathy in Animal Models, pages 439–451. Springer International Publishing, 2019. URL: http://dx.doi.org/10.1007/978-3-030-03095-7_25, doi:10.1007/978-3-030-03095-7_25. (1 citations) 10.1007/978-3-030-03095-7_25](https://doi.org/10.1007/978-3-030-03095-7_25)

[3. (Fanin2016Progress) Marina Fanin and Corrado Angelini. Progress and challenges in diagnosis of dysferlinopathy: dysferlinopathy diagnosis. Muscle & Nerve, 54(5):821–835, October 2016. URL: http://dx.doi.org/10.1002/mus.25367, doi:10.1002/mus.25367. (61 citations) 10.1002/mus.25367](https://doi.org/10.1002/mus.25367)

[4. (Cacciottolo2011Reverse) Mafalda Cacciottolo, Vincenzo Belcastro, Steve Laval, Kate Bushby, Diego di Bernardo, and Vincenzo Nigro. Reverse engineering gene network identifies new dysferlin-interacting proteins. Journal of Biological Chemistry, 286(7):5404–5413, February 2011. URL: http://dx.doi.org/10.1074/jbc.m110.173559, doi:10.1074/jbc.m110.173559. (45 citations) 10.1074/jbc.m110.173559](https://doi.org/10.1074/jbc.m110.173559)

[5. (Dominov2014A) Janice A. Dominov, Özgün Uyan, Peter C. Sapp, Diane McKenna‐Yasek, Babi R. R. Nallamilli, Madhuri Hegde, and Robert H. Brown. A novel dysferlin mutant pseudoexon bypassed with antisense oligonucleotides. Annals of Clinical and Translational Neurology, 1(9):703–720, September 2014. URL: http://dx.doi.org/10.1002/acn3.96, doi:10.1002/acn3.96. (34 citations) 10.1002/acn3.96](https://doi.org/10.1002/acn3.96)

[6. (Flix2013Dysferlin) Bàrbara Flix, Carolina de la Torre, Juan Castillo, Carme Casal, Isabel Illa, and Eduard Gallardo. Dysferlin interacts with calsequestrin-1, myomesin-2 and dynein in human skeletal muscle. The International Journal of Biochemistry & Cell Biology, 45(8):1927–1938, August 2013. URL: http://dx.doi.org/10.1016/j.biocel.2013.06.007, doi:10.1016/j.biocel.2013.06.007. (23 citations) 10.1016/j.biocel.2013.06.007](https://doi.org/10.1016/j.biocel.2013.06.007)

[7. (Vilchez2005Identification) Juan J. Vilchez, Pia Gallano, Eduard Gallardo, Adriana Lasa, Ricardo Rojas-García, Alba Freixas, Noemí De Luna, Francesc Calafell, Teresa Sevilla, Fernando Mayordomo, Montserrat Baiget, and Isabel Illa. Identification of a novel founder mutation in the dysf gene causing clinical variability in the spanish population. Archives of Neurology, 62(8):1256, August 2005. URL: http://dx.doi.org/10.1001/archneur.62.8.1256, doi:10.1001/archneur.62.8.1256. (74 citations) 10.1001/archneur.62.8.1256](https://doi.org/10.1001/archneur.62.8.1256)

[8. (Assadi2008Identification) Maziar Assadi, Thomas Schindler, Bernd Muller, John D Porter, Markus A Ruegg, and Hanno Langen. Identification of proteins interacting with dysferlin using the tandem affinity purification method. The Open Cell Development & Biology Journal, 1:17–23, June 2008. URL: http://dx.doi.org/10.2174/1874085500801010017, doi:10.2174/1874085500801010017. (4 citations) 10.2174/1874085500801010017](https://doi.org/10.2174/1874085500801010017)

[9. (Cárdenas2016Dysferlin) Ana M. Cárdenas, Arlek M. González-Jamett, Luis A. Cea, Jorge A. Bevilacqua, and Pablo Caviedes. Dysferlin function in skeletal muscle: possible pathological mechanisms and therapeutical targets in dysferlinopathies. Experimental Neurology, 283:246–254, September 2016. URL: http://dx.doi.org/10.1016/j.expneurol.2016.06.026, doi:10.1016/j.expneurol.2016.06.026. (70 citations) 10.1016/j.expneurol.2016.06.026](https://doi.org/10.1016/j.expneurol.2016.06.026)

[10. (Nguyen2005Dysferlin) Karine Nguyen, Guillaume Bassez, Rafaëlle Bernard, Martin Krahn, Véronique Labelle, Dominique Figarella-Branger, Jean Pouget, El Hadi Hammouda, Christophe Béroud, Andoni Urtizberea, Bruno Eymard, France Leturcq, and Nicolas Lévy. Dysferlin mutations in lgmd2b, miyoshi myopathy, and atypical dysferlinopathies. Human Mutation, 26(2):165–165, 2005. URL: http://dx.doi.org/10.1002/humu.9355, doi:10.1002/humu.9355. (143 citations) 10.1002/humu.9355](https://doi.org/10.1002/humu.9355)

[11. (Huang2006AHNAK) Yanchao Huang, Steven H. Laval, Alexandra Remoortere, Jacques Baudier, Chriselle Benaud, Louise V. B. Anderson, Volker Straub, Andre Deelder, Rune R. Frants, Johan T. Dunnen, Kate Bushby, and Silvere M. Maarel. Ahnak a novel component of the dysferlin protein complex, redistributes to the cytoplasm with dysferlin during skeletal muscle regeneration. The FASEB Journal, 21(3):732–742, December 2006. URL: http://dx.doi.org/10.1096/fj.06-6628com, doi:10.1096/fj.06-6628com. (189 citations) 10.1096/fj.06-6628com](https://doi.org/10.1096/fj.06-6628com)

[12. (de2010Proteomic) Antoine de Morrée, Paul J. Hensbergen, Herman H. H. B. M. van Haagen, Irina Dragan, André M. Deelder, Peter A. C. ’t Hoen, Rune R. Frants, and Silvère M. van der Maarel. Proteomic analysis of the dysferlin protein complex unveils its importance for sarcolemmal maintenance and integrity. PLoS ONE, 5(11):e13854, November 2010. URL: http://dx.doi.org/10.1371/journal.pone.0013854, doi:10.1371/journal.pone.0013854. (88 citations) 10.1371/journal.pone.0013854](https://doi.org/10.1371/journal.pone.0013854)

[13. (Wang2024Two) Lun Wang, Yan Zhou, Tiantian Wei, and Hongyao Huang. Two homozygous adjacent novel missense mutations in dysf gene caused dysferlinopathy due to splicing abnormalities. Frontiers in Genetics, June 2024. URL: http://dx.doi.org/10.3389/fgene.2024.1404611, doi:10.3389/fgene.2024.1404611. (0 citations) 10.3389/fgene.2024.1404611](https://doi.org/10.3389/fgene.2024.1404611)