Comprehensive Physiology Wiley Online Library

The Dystrophin Complex: Structure, Function, and Implications for Therapy

Full Article on Wiley Online Library



ABSTRACT

The dystrophin complex stabilizes the plasma membrane of striated muscle cells. Loss of function mutations in the genes encoding dystrophin, or the associated proteins, trigger instability of the plasma membrane, and myofiber loss. Mutations in dystrophin have been extensively cataloged, providing remarkable structure‐function correlation between predicted protein structure and clinical outcomes. These data have highlighted dystrophin regions necessary for in vivo function and fueled the design of viral vectors and now, exon skipping approaches for use in dystrophin restoration therapies. However, dystrophin restoration is likely more complex, owing to the role of the dystrophin complex as a broad cytoskeletal integrator. This review will focus on dystrophin restoration, with emphasis on the regions of dystrophin essential for interacting with its associated proteins and discuss the structural implications of these approaches. © 2015 American Physiological Society. Compr Physiol 5:1223‐1239, 2015.

Comprehensive Physiology offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images


Figure 1. Figure 1. Dystrophin‐glycoprotein complex (DGC). Dystrophin is a rod shape protein that links intracellular cytoskeleton network to transmembrane components of the DGC, including dystroglycan, sarcoglycans, and sarcospan. Dystroglycan is composed of two subunits, α and β. α‐Dystroglycan is an extracellular peripheral membrane protein and a receptor for laminin‐2, linking the DGC to the ECM. The sarcoglycans form a tight complex with sarcospan, strengthening the connection between α and β‐dystroglycans. Besides a structural role, the sarcoglycan‐sarcospan subcomplex is also involved in signal transduction and mechanoprotection. α‐Dystroglycan is heavily O‐glycosylated (straight lines) in the central mucin domain. β‐Dystroglycan and the sarcoglycans contain potential N‐glycosylation sites (branch). The syntrophins, dystrobrevins, and nNOS are recruited to the C‐terminus of dystrophin and participate in signal transduction pathways.
Figure 2. Figure 2. Dystrophin functional domains and mini‐/micro‐dystrophin constructs. (A) Dystrophin protein has four major functional domains. The N‐terminal actin‐binding domain (ABD1, shown in blue) contains two calponin‐homology (CH) motifs. The central rod domain is composed of 24 spectrin‐like repeats (R1‐R24, shown in white) interrupted by the proline‐rich hinges (H1‐H4, shown in yellow). A second actin‐binding domain (ABD2) spans R11‐R17. The cysteine‐rich domain (CR, shown in yellow) and part of H4 form the binding site for β‐dystroglycan (DgBD). The C‐terminus (CT, shown in gray) contains binding sites for syntrophins (SBD) and dystrobrevin (DbBD). (B) Domain structure of the internally truncated dystrophin constructs discussed in the text. Note that exons 17 to 48 deletions (Δ17‐48) retain a partial R19. The molecular weights are shown to the right of the constructs.
Figure 3. Figure 3. Phasing of spectrin repeats with dystrophin has functional consequences. (A) The central rod of dystrophin is composed of 24 spectrin‐like repeats. Each repeat unit is ∼110 aa in size and forms a triple α‐helical bundle; a and b form the long helix while c forms the short helix. (B) In the normal dystrophin protein, repeat 19 and repeat 20 is separated by hinge 3. (C) The exon Δ17‐48 deletion retains the last half of b helix and full c helix from R19 in the protein, producing an extra helical region that may disrupt the folding pattern of the protein. (D) The ΔH2‐R19 construct removes the partial R19 that is retained in the Δ17‐48 deletions, resulting in an overall structure identical to that of the normal protein. Maintaining the triple helical structure of each repeat is important for its molecular function. When expressed in the mdx mice, ΔH2‐R19 construct has a better rescue effects than the Δ17‐48 construct (). Furthermore, clinical observations show that BMD patients carrying deletions that disrupt repeat phasing develop cardiomyopathy 10 years earlier than those carrying deletions that retain the correct phasing of the repeat ().
Figure 4. Figure 4. The sarcoglycan complex. Six sarcoglycans have been identified in mammals. α‐ and ϵ‐sarcoglycans are type I transmembrane proteins and are ∼60% related. α‐ and ϵ‐sarcoglycan genes likely arose from a single gene duplication event since they also have an identical intron‐exon structure. There is a single gene related to both α‐ and ϵ‐sarcoglycan in invertebrates. γ‐, δ‐, and ζ‐ are type II transmembrane proteins. These three sarcoglycans have identical gene structure and are ∼70% similar in protein sequence. There is a single gene related to γ‐, δ‐, and ζ‐sarcoglycan in invertebrates, suggesting that they arose from multiple gene duplication events. β‐Sarcoglycan is also a type II transmembrane protein but is only weakly related to these sarcoglycans. Conserved cysteine residues at the C‐terminus of β, δ, γ, and ζ are necessary for intramolecular disulfide bond formation (). In striated muscle, the major sarcoglycan complex is composed of α‐, β‐, γ‐, and δ‐sarcoglycan (left). In vascular smooth muscle, the major sarcoglycan complex contains ϵ‐, β‐, ζ‐, and δ‐sarcoglycan (middle). In invertebrates (Drosophila and C elegans), there are only three sarcoglycans, α/ϵ‐, γ/δ/ζ‐, and β‐sarcoglycan (right).
Figure 5. Figure 5. Sarcoglycan complex assembly and sarcolemmal targeting. (A) The assembly of the sarcoglycan complex follows a specific path after protein translation. First, β‐sarcoglycan interacts with δ‐sarcoglycan to form the complex core. γ‐sarcoglycan then associates with the β‐δ core. Finally, α‐sarcoglycan completes the formation of the complex. Deficiency in any sarcoglycan gene impairs the complex formation and plasma membrane translocation. (B) The sarcoglycan complex formation occurs in the ER. From Golgi to the sarcolemma, the sarcoglycans become associates with dystroglycan and sarcospan. At the sarcolemma, dystrophin reinforces the membrane localization of the sarcoglycans. In the absence of dystrophin, the sarcoglycan complex is also lost from the sarcolemma.


Figure 1. Dystrophin‐glycoprotein complex (DGC). Dystrophin is a rod shape protein that links intracellular cytoskeleton network to transmembrane components of the DGC, including dystroglycan, sarcoglycans, and sarcospan. Dystroglycan is composed of two subunits, α and β. α‐Dystroglycan is an extracellular peripheral membrane protein and a receptor for laminin‐2, linking the DGC to the ECM. The sarcoglycans form a tight complex with sarcospan, strengthening the connection between α and β‐dystroglycans. Besides a structural role, the sarcoglycan‐sarcospan subcomplex is also involved in signal transduction and mechanoprotection. α‐Dystroglycan is heavily O‐glycosylated (straight lines) in the central mucin domain. β‐Dystroglycan and the sarcoglycans contain potential N‐glycosylation sites (branch). The syntrophins, dystrobrevins, and nNOS are recruited to the C‐terminus of dystrophin and participate in signal transduction pathways.


Figure 2. Dystrophin functional domains and mini‐/micro‐dystrophin constructs. (A) Dystrophin protein has four major functional domains. The N‐terminal actin‐binding domain (ABD1, shown in blue) contains two calponin‐homology (CH) motifs. The central rod domain is composed of 24 spectrin‐like repeats (R1‐R24, shown in white) interrupted by the proline‐rich hinges (H1‐H4, shown in yellow). A second actin‐binding domain (ABD2) spans R11‐R17. The cysteine‐rich domain (CR, shown in yellow) and part of H4 form the binding site for β‐dystroglycan (DgBD). The C‐terminus (CT, shown in gray) contains binding sites for syntrophins (SBD) and dystrobrevin (DbBD). (B) Domain structure of the internally truncated dystrophin constructs discussed in the text. Note that exons 17 to 48 deletions (Δ17‐48) retain a partial R19. The molecular weights are shown to the right of the constructs.


Figure 3. Phasing of spectrin repeats with dystrophin has functional consequences. (A) The central rod of dystrophin is composed of 24 spectrin‐like repeats. Each repeat unit is ∼110 aa in size and forms a triple α‐helical bundle; a and b form the long helix while c forms the short helix. (B) In the normal dystrophin protein, repeat 19 and repeat 20 is separated by hinge 3. (C) The exon Δ17‐48 deletion retains the last half of b helix and full c helix from R19 in the protein, producing an extra helical region that may disrupt the folding pattern of the protein. (D) The ΔH2‐R19 construct removes the partial R19 that is retained in the Δ17‐48 deletions, resulting in an overall structure identical to that of the normal protein. Maintaining the triple helical structure of each repeat is important for its molecular function. When expressed in the mdx mice, ΔH2‐R19 construct has a better rescue effects than the Δ17‐48 construct (). Furthermore, clinical observations show that BMD patients carrying deletions that disrupt repeat phasing develop cardiomyopathy 10 years earlier than those carrying deletions that retain the correct phasing of the repeat ().


Figure 4. The sarcoglycan complex. Six sarcoglycans have been identified in mammals. α‐ and ϵ‐sarcoglycans are type I transmembrane proteins and are ∼60% related. α‐ and ϵ‐sarcoglycan genes likely arose from a single gene duplication event since they also have an identical intron‐exon structure. There is a single gene related to both α‐ and ϵ‐sarcoglycan in invertebrates. γ‐, δ‐, and ζ‐ are type II transmembrane proteins. These three sarcoglycans have identical gene structure and are ∼70% similar in protein sequence. There is a single gene related to γ‐, δ‐, and ζ‐sarcoglycan in invertebrates, suggesting that they arose from multiple gene duplication events. β‐Sarcoglycan is also a type II transmembrane protein but is only weakly related to these sarcoglycans. Conserved cysteine residues at the C‐terminus of β, δ, γ, and ζ are necessary for intramolecular disulfide bond formation (). In striated muscle, the major sarcoglycan complex is composed of α‐, β‐, γ‐, and δ‐sarcoglycan (left). In vascular smooth muscle, the major sarcoglycan complex contains ϵ‐, β‐, ζ‐, and δ‐sarcoglycan (middle). In invertebrates (Drosophila and C elegans), there are only three sarcoglycans, α/ϵ‐, γ/δ/ζ‐, and β‐sarcoglycan (right).


Figure 5. Sarcoglycan complex assembly and sarcolemmal targeting. (A) The assembly of the sarcoglycan complex follows a specific path after protein translation. First, β‐sarcoglycan interacts with δ‐sarcoglycan to form the complex core. γ‐sarcoglycan then associates with the β‐δ core. Finally, α‐sarcoglycan completes the formation of the complex. Deficiency in any sarcoglycan gene impairs the complex formation and plasma membrane translocation. (B) The sarcoglycan complex formation occurs in the ER. From Golgi to the sarcolemma, the sarcoglycans become associates with dystroglycan and sarcospan. At the sarcolemma, dystrophin reinforces the membrane localization of the sarcoglycans. In the absence of dystrophin, the sarcoglycan complex is also lost from the sarcolemma.
References
 1.Adams ME, Kramarcy N, Krall SP, Rossi SG, Rotundo RL, Sealock R, Froehner SC. Absence of alpha‐syntrophin leads to structurally aberrant neuromuscular synapses deficient in utrophin. J Cell Biol 150: 1385‐1398, 2000.
 2.Aguiari P, Leo S, Zavan B, Vindigni V, Rimessi A, Bianchi K, Franzin C, Cortivo R, Rossato M, Vettor R, Abatangelo G, Pozzan T, Pinton P, Rizzuto R. High glucose induces adipogenic differentiation of muscle‐derived stem cells. Proc Natl Acad Sci U S A 105: 1226‐1231, 2008.
 3.Allen DG. Eccentric muscle damage: Mechanisms of early reduction of force. Acta Physiol Scand 171: 311‐319, 2001.
 4.Allikian MJ, Bhabha G, Dospoy P, Heydemann A, Ryder P, Earley JU, Wolf MJ, Rockman HA, McNally EM. Reduced life span with heart and muscle dysfunction in Drosophila sarcoglycan mutants. Hum Mol Genet 16: 2933‐2943, 2007.
 5.Allikian MJ, Hack AA, Mewborn S, Mayer U, McNally EM. Genetic compensation for sarcoglycan loss by integrin alpha7beta1 in muscle. J Cell Sci 117: 3821‐3830, 2004.
 6.Amann KJ, Renley BA, Ervasti JM. A cluster of basic repeats in the dystrophin rod domain binds F‐actin through an electrostatic interaction. J Biol Chem 273: 28419‐28423, 1998.
 7.Anastasi G. Sarcoglycan[s] are not muscle‐specific: Hypothetical roles. Ital J Anat Embryol 115: 19‐24, 2010.
 8.Anderson JT, Rogers RP, Jarrett HW. Ca2+‐calmodulin binds to the carboxyl‐terminal domain of dystrophin. J Biol Chem 271: 6605‐6610, 1996.
 9.Anthony K, Arechavala‐Gomeza V, Ricotti V, Torelli S, Feng L, Janghra N, Tasca G, Guglieri M, Barresi R, Armaroli A, Ferlini A, Bushby K, Straub V, Ricci E, Sewry C, Morgan J, Muntoni F. Biochemical characterization of patients with in‐frame or out‐of‐frame DMD deletions pertinent to exon 44 or 45 skipping. JAMA Neurol 71: 32‐40, 2014.
 10.Anthony K, Cirak S, Torelli S, Tasca G, Feng L, Arechavala‐Gomeza V, Armaroli A, Guglieri M, Straathof CS, Verschuuren JJ, Aartsma‐Rus A, Helderman‐van den Enden P, Bushby K, Straub V, Sewry C, Ferlini A, Ricci E, Morgan JE, Muntoni F. Dystrophin quantification and clinical correlations in Becker muscular dystrophy: Implications for clinical trials. Brain 134: 3547‐3559, 2011.
 11.Aoki Y, Yokota T, Nagata T, Nakamura A, Tanihata J, Saito T, Duguez SM, Nagaraju K, Hoffman EP, Partridge T, Takeda S. Bodywide skipping of exons 45‐55 in dystrophic mdx52 mice by systemic antisense delivery. Proc Natl Acad Sci U S A 109: 13763‐13768, 2012.
 12.Aplin AE, Howe A, Alahari SK, Juliano RL. Signal transduction and signal modulation by cell adhesion receptors: The role of integrins, cadherins, immunoglobulin‐cell adhesion molecules, and selectins. Pharmacol Rev 50: 197‐263, 1998.
 13.Araishi K, Sasaoka T, Imamura M, Noguchi S, Hama H, Wakabayashi E, Yoshida M, Hori T, Ozawa E. Loss of the sarcoglycan complex and sarcospan leads to muscular dystrophy in beta‐sarcoglycan‐deficient mice. Hum Mol Genet 8: 1589‐1598, 1999.
 14.Athanasopoulos T, Graham IR, Foster H, Dickson G. Recombinant adeno‐associated viral (rAAV) vectors as therapeutic tools for Duchenne muscular dystrophy (DMD). Gene Ther 11(Suppl 1): S109‐121, 2004.
 15.Ayalon G, Davis JQ, Scotland PB, Bennett V. An ankyrin‐based mechanism for functional organization of dystrophin and dystroglycan. Cell 135: 1189‐1200, 2008.
 16.Banks GB, Combs AC, Chamberlain JR, Chamberlain JS. Molecular and cellular adaptations to chronic myotendinous strain injury in mdx mice expressing a truncated dystrophin. Hum Mol Genet 17: 3975‐3986, 2008.
 17.Banks GB, Gregorevic P, Allen JM, Finn EE, Chamberlain JS. Functional capacity of dystrophins carrying deletions in the N‐terminal actin‐binding domain. Hum Mol Genet 16: 2105‐2113, 2007.
 18.Banks GB, Judge LM, Allen JM, Chamberlain JS. The polyproline site in hinge 2 influences the functional capacity of truncated dystrophins. PLoS Genet 6: e1000958, 2010.
 19.Barton ER. Impact of sarcoglycan complex on mechanical signal transduction in murine skeletal muscle. Am J Physiol Cell Physiol 290: C411‐C419, 2006.
 20.Barton ER. Restoration of gamma‐sarcoglycan localization and mechanical signal transduction are independent in murine skeletal muscle. J Biol Chem 285: 17263‐17270, 2010.
 21.Belanto JJ, Mader TL, Eckhoff MD, Strandjord DM, Banks GB, Gardner MK, Lowe DA, Ervasti JM. Microtubule binding distinguishes dystrophin from utrophin. Proc Natl Acad Sci U S A 111: 5723‐5728, 2014.
 22.Beroud C, Tuffery‐Giraud S, Matsuo M, Hamroun D, Humbertclaude V, Monnier N, Moizard MP, Voelckel MA, Calemard LM, Boisseau P, Blayau M, Philippe C, Cossee M, Pages M, Rivier F, Danos O, Garcia L, Claustres M. Multiexon skipping leading to an artificial DMD protein lacking amino acids from exons 45 through 55 could rescue up to 63% of patients with Duchenne muscular dystrophy. Hum Mutat 28: 196‐202, 2007.
 23.Bhattacharya S, Das A, Ghosh S, Dasgupta R, Bagchi A. Hypoglycosylation of dystroglycan due to T192M mutation: A molecular insight behind the fact. Gene 537: 108‐114, 2014.
 24.Bhosle RC, Michele DE, Campbell KP, Li Z, Robson RM. Interactions of intermediate filament protein synemin with dystrophin and utrophin. Biochem Biophys Res Commun 346: 768‐777, 2006.
 25.Bies RD, Caskey CT, Fenwick R. An intact cysteine‐rich domain is required for dystrophin function. J Clin Invest 90: 666‐672, 1992.
 26.Blaeser A, Sparks S, Brown SC, Campbell K, Lu Q. Third International Workshop for Glycosylation Defects in Muscular Dystrophies, 18‐19 April 2013, Charlotte, USA. Brain Pathol 24: 280‐284, 2014.
 27.Blake DJ. Dystrobrevin dynamics in muscle‐cell signalling: A possible target for therapeutic intervention in Duchenne muscular dystrophy? Neuromuscul Disord 12(Suppl 1): S110‐117, 2002.
 28.Blake DJ, Tinsley JM, Davies KE, Knight AE, Winder SJ, Kendrick‐Jones J. Coiled‐coil regions in the carboxy‐terminal domains of dystrophin and related proteins: Potentials for protein‐protein interactions. Trends Biochem Sci 20: 133‐135, 1995.
 29.Brancaccio A, Schulthess T, Gesemann M, Engel J. Electron microscopic evidence for a mucin‐like region in chick muscle alpha‐dystroglycan. FEBS Lett 368: 139‐142, 1995.
 30.Brancaccio A, Schulthess T, Gesemann M, Engel J. The N‐terminal region of alpha‐dystroglycan is an autonomous globular domain. Eur J Biochem 246: 166‐172, 1997.
 31.Brenman JE, Chao DS, Gee SH, McGee AW, Craven SE, Santillano DR, Wu Z, Huang F, Xia H, Peters MF, Froehner SC, Bredt DS. Interaction of nitric oxide synthase with the postsynaptic density protein PSD‐95 and alpha1‐syntrophin mediated by PDZ domains. Cell 84: 757‐767, 1996.
 32.Broderick MJ, Winder SJ. Spectrin, alpha‐actinin, and dystrophin. Adv Protein Chem 70: 203‐246, 2005.
 33.Butler MH, Douville K, Murnane AA, Kramarcy NR, Cohen JB, Sealock R, Froehner SC. Association of the Mr 58,000 postsynaptic protein of electric tissue with Torpedo dystrophin and the Mr 87,000 postsynaptic protein. J Biol Chem 267: 6213‐6218, 1992.
 34.Buysse K, Riemersma M, Powell G, van Reeuwijk J, Chitayat D, Roscioli T, Kamsteeg EJ, van den Elzen C, van Beusekom E, Blaser S, Babul‐Hirji R, Halliday W, Wright GJ, Stemple DL, Lin YY, Lefeber DJ, van Bokhoven H. Missense mutations in beta‐1,3‐N‐acetylglucosaminyltransferase 1 (B3GNT1) cause Walker‐Warburg syndrome. Hum Mol Genet 22: 1746‐1754, 2013.
 35.Carss KJ, Stevens E, Foley AR, Cirak S, Riemersma M, Torelli S, Hoischen A, Willer T, van Scherpenzeel M, Moore SA, Messina S, Bertini E, Bonnemann CG, Abdenur JE, Grosmann CM, Kesari A, Punetha J, Quinlivan R, Waddell LB, Young HK, Wraige E, Yau S, Brodd L, Feng L, Sewry C, MacArthur DG, North KN, Hoffman E, Stemple DL, Hurles ME, van Bokhoven H, Campbell KP, Lefeber DJ, Lin YY, Muntoni F. Mutations in GDP‐mannose pyrophosphorylase B cause congenital and limb‐girdle muscular dystrophies associated with hypoglycosylation of alpha‐dystroglycan. Am J Hum Genet 93: 29‐41, 2013.
 36.Cartaud A, Coutant S, Petrucci TC, Cartaud J. Evidence for in situ and in vitro association between beta‐dystroglycan and the subsynaptic 43K rapsyn protein. Consequence for acetylcholine receptor clustering at the synapse. J Biol Chem 273: 11321‐11326, 1998.
 37.Cassano M, Dellavalle A, Tedesco FS, Quattrocelli M, Crippa S, Ronzoni F, Salvade A, Berardi E, Torrente Y, Cossu G, Sampaolesi M. Alpha sarcoglycan is required for FGF‐dependent myogenic progenitor cell proliferation in vitro and in vivo. Development 138: 4523‐4533, 2011.
 38.Chambers SP, Anderson LV, Maguire GM, Dodd A, Love DR. Sarcoglycans of the zebrafish: Orthology and localization to the sarcolemma and myosepta of muscle. Biochem Biophys Res Commun 303: 488‐495, 2003.
 39.Chan YM, Bonnemann CG, Lidov HG, Kunkel LM. Molecular organization of sarcoglycan complex in mouse myotubes in culture. J Cell Biol 143: 2033‐2044, 1998.
 40.Chen J, Shi W, Zhang Y, Sokol R, Cai H, Lun M, Moore BF, Farber MJ, Stepanchick JS, Bonnemann CG, Chan YM. Identification of functional domains in sarcoglycans essential for their interaction and plasma membrane targeting. Exp Cell Res 312: 1610‐1625, 2006.
 41.Chen J, Skinner MA, Shi W, Yu QC, Wildeman AG, Chan YM. The 16 kDa subunit of vacuolar H+‐ATPase is a novel sarcoglycan‐interacting protein. Biochim Biophys Acta 1772: 570‐579, 2007.
 42.Cheung EC, Slack RS. Emerging role for ERK as a key regulator of neuronal apoptosis. Sci STKE 2004: PE45, 2004.
 43.Chung W, Campanelli JT. WW and EF hand domains of dystrophin‐family proteins mediate dystroglycan binding. Mol Cell Biol Res Commun 2: 162‐171, 1999.
 44.Crosbie RH, Heighway J, Venzke DP, Lee JC, Campbell KP. Sarcospan, the 25‐kDa transmembrane component of the dystrophin‐glycoprotein complex. J Biol Chem 272: 31221‐31224, 1997.
 45.Crosbie RH, Lebakken CS, Holt KH, Venzke DP, Straub V, Lee JC, Grady RM, Chamberlain JS, Sanes JR, Campbell KP. Membrane targeting and stabilization of sarcospan is mediated by the sarcoglycan subcomplex. J Cell Biol 145: 153‐165, 1999.
 46.Crosbie RH, Lim LE, Moore SA, Hirano M, Hays AP, Maybaum SW, Collin H, Dovico SA, Stolle CA, Fardeau M, Tome FM, Campbell KP. Molecular and genetic characterization of sarcospan: Insights into sarcoglycan‐sarcospan interactions. Hum Mol Genet 9: 2019‐2027, 2000.
 47.Dalkilic I, Kunkel LM. Muscular dystrophies: Genes to pathogenesis. Curr Opin Genet Dev 13: 231‐238, 2003.
 48.Danialou G, Comtois AS, Dudley R, Karpati G, Vincent G, Des Rosiers C, Petrof BJ. Dystrophin‐deficient cardiomyocytes are abnormally vulnerable to mechanical stress‐induced contractile failure and injury. FASEB J 15: 1655‐1657, 2001.
 49.Deconinck AE, Rafael JA, Skinner JA, Brown SC, Potter AC, Metzinger L, Watt DJ, Dickson JG, Tinsley JM, Davies KE. Utrophin‐dystrophin‐deficient mice as a model for Duchenne muscular dystrophy. Cell 90: 717‐727, 1997.
 50.Di Costanzo S, Balasubramanian A, Pond HL, Rozkalne A, Pantaleoni C, Saredi S, Gupta VA, Sunu CM, Yu TW, Kang PB, Salih MA, Mora M, Gussoni E, Walsh CA, Manzini MC. POMK mutations disrupt muscle development leading to a spectrum of neuromuscular presentations. Hum Mol Genet 23: 5781‐5792, 2014.
 51.Dressman D, Araishi K, Imamura M, Sasaoka T, Liu LA, Engvall E, Hoffman EP. Delivery of alpha‐ and beta‐sarcoglycan by recombinant adeno‐associated virus: Efficient rescue of muscle, but differential toxicity. Hum Gene Ther 13: 1631‐1646, 2002.
 52.Dwyer TM, Froehner SC. Direct binding of Torpedo syntrophin to dystrophin and the 87 kDa dystrophin homologue. FEBS Lett 375: 91‐94, 1995.
 53.England SB, Nicholson LV, Johnson MA, Forrest SM, Love DR, Zubrzycka‐Gaarn EE, Bulman DE, Harris JB, Davies KE. Very mild muscular dystrophy associated with the deletion of 46% of dystrophin. Nature 343: 180‐182, 1990.
 54.Ervasti JM, Campbell KP. A role for the dystrophin‐glycoprotein complex as a transmembrane linker between laminin and actin. J Cell Biol 122: 809‐823, 1993.
 55.Ervasti JM, Ohlendieck K, Kahl SD, Gaver MG, Campbell KP. Deficiency of a glycoprotein component of the dystrophin complex in dystrophic muscle. Nature 345: 315‐319, 1990.
 56.Fanin M, Angelini C. Defective assembly of sarcoglycan complex in patients with beta‐sarcoglycan gene mutations. Study of aneural and innervated cultured myotubes. Neuropathol Appl Neurobiol 28: 190‐199, 2002.
 57.Ferreiro V, Giliberto F, Muniz GM, Francipane L, Marzese DM, Mampel A, Roque M, Frechtel GD, Szijan I. Asymptomatic Becker muscular dystrophy in a family with a multiexon deletion. Muscle Nerve 39: 239‐243, 2009.
 58.Flanigan KM, Dunn DM, von Niederhausern A, Soltanzadeh P, Gappmaier E, Howard MT, Sampson JB, Mendell JR, Wall C, King WM, Pestronk A, Florence JM, Connolly AM, Mathews KD, Stephan CM, Laubenthal KS, Wong BL, Morehart PJ, Meyer A, Finkel RS, Bonnemann CG, Medne L, Day JW, Dalton JC, Margolis MK, Hinton VJ, Weiss RB. Mutational spectrum of DMD mutations in dystrophinopathy patients: Application of modern diagnostic techniques to a large cohort. Hum Mutat 30: 1657‐1666, 2009.
 59.Flanigan KM, Dunn DM, von Niederhausern A, Soltanzadeh P, Howard MT, Sampson JB, Swoboda KJ, Bromberg MB, Mendell JR, Taylor LE, Anderson CB, Pestronk A, Florence JM, Connolly AM, Mathews KD, Wong B, Finkel RS, Bonnemann CG, Day JW, McDonald C, Weiss RB. Nonsense mutation‐associated Becker muscular dystrophy: Interplay between exon definition and splicing regulatory elements within the DMD gene. Hum Mutat 32: 299‐308, 2011.
 60.Galbiati F, Razani B, Lisanti MP. Caveolae and caveolin‐3 in muscular dystrophy. Trends Mol Med 7: 435‐441, 2001.
 61.Gee SH, Montanaro F, Lindenbaum MH, Carbonetto S. Dystroglycan‐alpha, a dystrophin‐associated glycoprotein, is a functional agrin receptor. Cell 77: 675‐686, 1994.
 62.Ginjaar IB, Kneppers AL, v d Meulen JD, Anderson LV, Bremmer‐Bout M, van Deutekom JC, Weegenaar J, den Dunnen JT, Bakker E. Dystrophin nonsense mutation induces different levels of exon 29 skipping and leads to variable phenotypes within one BMD family. Eur J Hum Genet 8: 793‐796, 2000.
 63.Goemans NM, Tulinius M, van den Akker JT, Burm BE, Ekhart PF, Heuvelmans N, Holling T, Janson AA, Platenburg GJ, Sipkens JA, Sitsen JM, Aartsma‐Rus A, van Ommen GJ, Buyse G, Darin N, Verschuuren JJ, Campion GV, de Kimpe SJ, van Deutekom JC. Systemic administration of PRO051 in Duchenne's muscular dystrophy. N Engl J Med 364: 1513‐1522, 2011.
 64.Grady RM, Akaaboune M, Cohen AL, Maimone MM, Lichtman JW, Sanes JR. Tyrosine‐phosphorylated and nonphosphorylated isoforms of alpha‐dystrobrevin: Roles in skeletal muscle and its neuromuscular and myotendinous junctions. J Cell Biol 160: 741‐752, 2003.
 65.Grady RM, Grange RW, Lau KS, Maimone MM, Nichol MC, Stull JT, Sanes JR. Role for alpha‐dystrobrevin in the pathogenesis of dystrophin‐dependent muscular dystrophies. Nat Cell Biol 1: 215‐220, 1999.
 66.Grady RM, Zhou H, Cunningham JM, Henry MD, Campbell KP, Sanes JR. Maturation and maintenance of the neuromuscular synapse: Genetic evidence for roles of the dystrophin–glycoprotein complex. Neuron 25: 279‐293, 2000.
 67.Griffin MA, Feng H, Tewari M, Acosta P, Kawana M, Sweeney HL, Discher DE. gamma‐Sarcoglycan deficiency increases cell contractility, apoptosis and MAPK pathway activation but does not affect adhesion. J Cell Sci 118: 1405‐1416, 2005.
 68.Grisoni K, Martin E, Gieseler K, Mariol MC, Segalat L. Genetic evidence for a dystrophin‐glycoprotein complex (DGC) in Caenorhabditis elegans. Gene 294: 77‐86, 2002.
 69.Groh S, Zong H, Goddeeris MM, Lebakken CS, Venzke D, Pessin JE, Campbell KP. Sarcoglycan complex: Implications for metabolic defects in muscular dystrophies. J Biol Chem 284: 19178‐19182, 2009.
 70.Guo C, Willem M, Werner A, Raivich G, Emerson M, Neyses L, Mayer U. Absence of alpha 7 integrin in dystrophin‐deficient mice causes a myopathy similar to Duchenne muscular dystrophy. Hum Mol Genet 15: 989‐998, 2006.
 71.Guyon JR, Kudryashova E, Potts A, Dalkilic I, Brosius MA, Thompson TG, Beckmann JS, Kunkel LM, Spencer MJ. Calpain 3 cleaves filamin C and regulates its ability to interact with gamma‐ and delta‐sarcoglycans. Muscle Nerve 28: 472‐483, 2003.
 72.Hack AA, Cordier L, Shoturma DI, Lam MY, Sweeney HL, McNally EM. Muscle degeneration without mechanical injury in sarcoglycan deficiency. Proc Natl Acad Sci U S A 96: 10723‐10728, 1999.
 73.Hack AA, Lam MY, Cordier L, Shoturma DI, Ly CT, Hadhazy MA, Hadhazy MR, Sweeney HL, McNally EM. Differential requirement for individual sarcoglycans and dystrophin in the assembly and function of the dystrophin‐glycoprotein complex. J Cell Sci 113(Pt 14): 2535‐2544, 2000.
 74.Hack AA, Ly CT, Jiang F, Clendenin CJ, Sigrist KS, Wollmann RL, McNally EM. Gamma‐sarcoglycan deficiency leads to muscle membrane defects and apoptosis independent of dystrophin. J Cell Biol 142: 1279‐1287, 1998.
 75.Hackman P, Juvonen V, Sarparanta J, Penttinen M, Aarimaa T, Uusitalo M, Auranen M, Pihko H, Alen R, Junes M, Lonnqvist T, Kalimo H, Udd B. Enrichment of the R77C alpha‐sarcoglycan gene mutation in Finnish LGMD2D patients. Muscle Nerve 31: 199‐204, 2005.
 76.Hara Y, Balci‐Hayta B, Yoshida‐Moriguchi T, Kanagawa M, Beltran‐Valero de Bernabe D, Gundesli H, Willer T, Satz JS, Crawford RW, Burden SJ, Kunz S, Oldstone MB, Accardi A, Talim B, Muntoni F, Topaloglu H, Dincer P, Campbell KP. A dystroglycan mutation associated with limb‐girdle muscular dystrophy. N Engl J Med 364: 939‐946, 2011.
 77.Hara Y, Kanagawa M, Kunz S, Yoshida‐Moriguchi T, Satz JS, Kobayashi YM, Zhu Z, Burden SJ, Oldstone MB, Campbell KP. Like‐acetylglucosaminyltransferase (LARGE)‐dependent modification of dystroglycan at Thr‐317/319 is required for laminin binding and arenavirus infection. Proc Natl Acad Sci U S A 108: 17426‐17431, 2011.
 78.Harada H, Andersen JS, Mann M, Terada N, Korsmeyer SJ. p70S6 kinase signals cell survival as well as growth, inactivating the pro‐apoptotic molecule BAD. Proc Natl Acad Sci U S A 98: 9666‐9670, 2001.
 79.Harper SQ, Hauser MA, DelloRusso C, Duan D, Crawford RW, Phelps SF, Harper HA, Robinson AS, Engelhardt JF, Brooks SV, Chamberlain JS. Modular flexibility of dystrophin: Implications for gene therapy of Duchenne muscular dystrophy. Nat Med 8: 253‐261, 2002.
 80.Hasegawa M, Cuenda A, Spillantini MG, Thomas GM, Buee‐Scherrer V, Cohen P, Goedert M. Stress‐activated protein kinase‐3 interacts with the PDZ domain of alpha1‐syntrophin. A mechanism for specific substrate recognition. J Biol Chem 274: 12626‐12631, 1999.
 81.Hodges BL, Hayashi YK, Nonaka I, Wang W, Arahata K, Kaufman SJ. Altered expression of the alpha7beta1 integrin in human and murine muscular dystrophies. J Cell Sci 110(Pt 22): 2873‐2881, 1997.
 82.Hoffman EP, Brown RH, Jr., Kunkel LM. Dystrophin: The protein product of the Duchenne muscular dystrophy locus. Cell 51: 919‐928, 1987.
 83.Hoffman EP, Kunkel LM, Angelini C, Clarke A, Johnson M, Harris JB. Improved diagnosis of Becker muscular dystrophy by dystrophin testing. Neurology 39: 1011‐1017, 1989.
 84.Hornberger TA, Stuppard R, Conley KE, Fedele MJ, Fiorotto ML, Chin ER, Esser KA. Mechanical stimuli regulate rapamycin‐sensitive signalling by a phosphoinositide 3‐kinase‐, protein kinase B‐ and growth factor‐independent mechanism. Biochem J 380: 795‐804, 2004.
 85.Huang PL, Dawson TM, Bredt DS, Snyder SH, Fishman MC. Targeted disruption of the neuronal nitric oxide synthase gene. Cell 75: 1273‐1286, 1993.
 86.Ibraghimov‐Beskrovnaya O, Ervasti JM, Leveille CJ, Slaughter CA, Sernett SW, Campbell KP. Primary structure of dystrophin‐associated glycoproteins linking dystrophin to the extracellular matrix. Nature 355: 696‐702, 1992.
 87.Ichida F, Tsubata S, Bowles KR, Haneda N, Uese K, Miyawaki T, Dreyer WJ, Messina J, Li H, Bowles NE, Towbin JA. Novel gene mutations in patients with left ventricular noncompaction or Barth syndrome. Circulation 103: 1256‐1263, 2001.
 88.Ilsley JL, Sudol M, Winder SJ. The WW domain: Linking cell signalling to the membrane cytoskeleton. Cell Signal 14: 183‐189, 2002.
 89.Imamura M, Mochizuki Y, Engvall E, Takeda S. Epsilon‐sarcoglycan compensates for lack of alpha‐sarcoglycan in a mouse model of limb‐girdle muscular dystrophy. Hum Mol Genet 14: 775‐783, 2005.
 90.Jefferies JL, Eidem BW, Belmont JW, Craigen WJ, Ware SM, Fernbach SD, Neish SR, Smith EO, Towbin JA. Genetic predictors and remodeling of dilated cardiomyopathy in muscular dystrophy. Circulation 112: 2799‐2804, 2005.
 91.Kaspar RW, Allen HD, Ray WC, Alvarez CE, Kissel JT, Pestronk A, Weiss RB, Flanigan KM, Mendell JR, Montanaro F. Analysis of dystrophin deletion mutations predicts age of cardiomyopathy onset in becker muscular dystrophy. Circ Cardiovasc Genet 2: 544‐551, 2009.
 92.Khairallah RJ, Shi G, Sbrana F, Prosser BL, Borroto C, Mazaitis MJ, Hoffman EP, Mahurkar A, Sachs F, Sun Y, Chen YW, Raiteri R, Lederer WJ, Dorsey SG, Ward CW. Microtubules underlie dysfunction in duchenne muscular dystrophy. Sci Signal 5: ra56, 2012.
 93.Kim DS, Hayashi YK, Matsumoto H, Ogawa M, Noguchi S, Murakami N, Sakuta R, Mochizuki M, Michele DE, Campbell KP, Nonaka I, Nishino I. POMT1 mutation results in defective glycosylation and loss of laminin‐binding activity in alpha‐DG. Neurology 62: 1009‐1011, 2004.
 94.Kim MH, Kay DI, Rudra RT, Chen BM, Hsu N, Izumiya Y, Martinez L, Spencer MJ, Walsh K, Grinnell AD, Crosbie RH. Myogenic Akt signaling attenuates muscular degeneration, promotes myofiber regeneration and improves muscle function in dystrophin‐deficient mdx mice. Hum Mol Genet 20: 1324‐1338, 2011.
 95.Koenig M, Beggs AH, Moyer M, Scherpf S, Heindrich K, Bettecken T, Meng G, Muller CR, Lindlof M, Kaariainen H, et al. The molecular basis for Duchenne versus Becker muscular dystrophy: Correlation of severity with type of deletion. Am J Hum Genet 45: 498‐506, 1989.
 96.Koenig M, Hoffman EP, Bertelson CJ, Monaco AP, Feener C, Kunkel LM. Complete cloning of the Duchenne muscular dystrophy (DMD) cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals. Cell 50: 509‐517, 1987.
 97.Koenig M, Kunkel LM. Detailed analysis of the repeat domain of dystrophin reveals four potential hinge segments that may confer flexibility. J Biol Chem 265: 4560‐4566, 1990.
 98.Koenig M, Monaco AP, Kunkel LM. The complete sequence of dystrophin predicts a rod‐shaped cytoskeletal protein. Cell 53: 219‐228, 1988.
 99.Korenbaum E, Rivero F. Calponin homology domains at a glance. J Cell Sci 115: 3543‐3545, 2002.
 100.Lai Y, Thomas GD, Yue Y, Yang HT, Li D, Long C, Judge L, Bostick B, Chamberlain JS, Terjung RL, Duan D. Dystrophins carrying spectrin‐like repeats 16 and 17 anchor nNOS to the sarcolemma and enhance exercise performance in a mouse model of muscular dystrophy. J Clin Invest 119: 624‐635, 2009.
 101.Le Rumeur E, Fichou Y, Pottier S, Gaboriau F, Rondeau‐Mouro C, Vincent M, Gallay J, Bondon A. Interaction of dystrophin rod domain with membrane phospholipids. Evidence of a close proximity between tryptophan residues and lipids. J Biol Chem 278: 5993‐6001, 2003.
 102.Lebakken CS, Venzke DP, Hrstka RF, Consolino CM, Faulkner JA, Williamson RA, Campbell KP. Sarcospan‐deficient mice maintain normal muscle function. Mol Cell Biol 20: 1669‐1677, 2000.
 103.Liechti‐Gallati S, Koenig M, Kunkel LM, Frey D, Boltshauser E, Schneider V, Braga S, Moser H. Molecular deletion patterns in Duchenne and Becker type muscular dystrophy. Hum Genet 81: 343‐348, 1989.
 104.Longman C, Brockington M, Torelli S, Jimenez‐Mallebrera C, Kennedy C, Khalil N, Feng L, Saran RK, Voit T, Merlini L, Sewry CA, Brown SC, Muntoni F. Mutations in the human LARGE gene cause MDC1D, a novel form of congenital muscular dystrophy with severe mental retardation and abnormal glycosylation of alpha‐dystroglycan. Hum Mol Genet 12: 2853‐2861, 2003.
 105.Madhavan R, Jarrett HW. Phosphorylation of dystrophin and alpha‐syntrophin by Ca(2+)‐calmodulin dependent protein kinase II. Biochim Biophys Acta 1434: 260‐274, 1999.
 106.Madhavan R, Massom LR, Jarrett HW. Calmodulin specifically binds three proteins of the dystrophin‐glycoprotein complex. Biochem Biophys Res Commun 185: 753‐759, 1992.
 107.Marshall JL, Chou E, Oh J, Kwok A, Burkin DJ, Crosbie‐Watson RH. Dystrophin and utrophin expression require sarcospan: Loss of alpha7 integrin exacerbates a newly discovered muscle phenotype in sarcospan‐null mice. Hum Mol Genet 21: 4378‐4393, 2012.
 108.Marshall JL, Crosbie‐Watson RH. Sarcospan: A small protein with large potential for Duchenne muscular dystrophy. Skelet Muscle 3: 1, 2013.
 109.Marshall JL, Holmberg J, Chou E, Ocampo AC, Oh J, Lee J, Peter AK, Martin PT, Crosbie‐Watson RH. Sarcospan‐dependent Akt activation is required for utrophin expression and muscle regeneration. J Cell Biol 197: 1009‐1027, 2012.
 110.McNally EM, Pytel P. Muscle diseases: The muscular dystrophies. Annu Rev Pathol 2: 87‐109, 2007.
 111.Michele DE, Barresi R, Kanagawa M, Saito F, Cohn RD, Satz JS, Dollar J, Nishino I, Kelley RI, Somer H, Straub V, Mathews KD, Moore SA, Campbell KP. Post‐translational disruption of dystroglycan‐ligand interactions in congenital muscular dystrophies. Nature 418: 417‐422, 2002.
 112.Miller G, Peter AK, Espinoza E, Heighway J, Crosbie RH. Over‐expression of Microspan, a novel component of the sarcoplasmic reticulum, causes severe muscle pathology with triad abnormalities. J Muscle Res Cell Motil 27: 545‐558, 2006.
 113.Miller G, Wang EL, Nassar KL, Peter AK, Crosbie RH. Structural and functional analysis of the sarcoglycan‐sarcospan subcomplex. Exp Cell Res 313: 639‐651, 2007.
 114.Moorwood C, Philippou A, Spinazzola J, Keyser B, Macarak EJ, Barton ER. Absence of gamma‐sarcoglycan alters the response of p70S6 kinase to mechanical perturbation in murine skeletal muscle. Skelet Muscle 4: 13, 2014.
 115.Muntoni F. Journey into muscular dystrophies caused by abnormal glycosylation. Acta Myol 23: 79‐84, 2004.
 116.Nakamura A, Yoshida K, Fukushima K, Ueda H, Urasawa N, Koyama J, Yazaki Y, Yazaki M, Sakai T, Haruta S, Takeda S, Ikeda S. Follow‐up of three patients with a large in‐frame deletion of exons 45‐55 in the Duchenne muscular dystrophy (DMD) gene. J Clin Neurosci 15: 757‐763, 2008.
 117.Newey SE, Benson MA, Ponting CP, Davies KE, Blake DJ. Alternative splicing of dystrobrevin regulates the stoichiometry of syntrophin binding to the dystrophin protein complex. Curr Biol 10: 1295‐1298, 2000.
 118.Nigro V, Savarese M. Genetic basis of limb‐girdle muscular dystrophies: The 2014 update. Acta Myol 33: 1‐12, 2014.
 119.Noguchi S, Wakabayashi E, Imamura M, Yoshida M, Ozawa E. Formation of sarcoglycan complex with differentiation in cultured myocytes. Eur J Biochem 267: 640‐648, 2000.
 120.Oak SA, Russo K, Petrucci TC, Jarrett HW. Mouse alpha1‐syntrophin binding to Grb2: Further evidence of a role for syntrophin in cell signaling. Biochemistry 40: 11270‐11278, 2001.
 121.Ogawa M, Nakamura N, Nakayama Y, Kurosaka A, Manya H, Kanagawa M, Endo T, Furukawa K, Okajima T. GTDC2 modifies O‐mannosylated alpha‐dystroglycan in the endoplasmic reticulum to generate N‐acetyl glucosamine epitopes reactive with CTD110.6 antibody. Biochem Biophys Res Commun 440: 88‐93, 2013.
 122.Peter AK, Marshall JL, Crosbie RH. Sarcospan reduces dystrophic pathology: Stabilization of the utrophin‐glycoprotein complex. J Cell Biol 183: 419‐427, 2008.
 123.Peter AK, Miller G, Crosbie RH. Disrupted mechanical stability of the dystrophin‐glycoprotein complex causes severe muscular dystrophy in sarcospan transgenic mice. J Cell Sci 120: 996‐1008, 2007.
 124.Petrof BJ, Shrager JB, Stedman HH, Kelly AM, Sweeney HL. Dystrophin protects the sarcolemma from stresses developed during muscle contraction. Proc Natl Acad Sci U S A 90: 3710‐3714, 1993.
 125.Phelps SF, Hauser MA, Cole NM, Rafael JA, Hinkle RT, Faulkner JA, Chamberlain JS. Expression of full‐length and truncated dystrophin mini‐genes in transgenic mdx mice. Hum Mol Genet 4: 1251‐1258, 1995.
 126.Ponting CP, Blake DJ, Davies KE, Kendrick‐Jones J, Winder SJ. ZZ and TAZ: New putative zinc fingers in dystrophin and other proteins. Trends Biochem Sci 21: 11‐13, 1996.
 127.Porter GA, Dmytrenko GM, Winkelmann JC, Bloch RJ. Dystrophin colocalizes with beta‐spectrin in distinct subsarcolemmal domains in mammalian skeletal muscle. J Cell Biol 117: 997‐1005, 1992.
 128.Prins KW, Humston JL, Mehta A, Tate V, Ralston E, Ervasti JM. Dystrophin is a microtubule‐associated protein. J Cell Biol 186: 363‐369, 2009.
 129.Recan D, Chafey P, Leturcq F, Hugnot JP, Vincent N, Tome F, Collin H, Simon D, Czernichow P, Nicholson LV, et al. Are cysteine‐rich and COOH‐terminal domains of dystrophin critical for sarcolemmal localization? J Clin Invest 89: 712‐716, 1992.
 130.Rentschler S, Linn H, Deininger K, Bedford MT, Espanel X, Sudol M. The WW domain of dystrophin requires EF‐hands region to interact with beta‐dystroglycan. Biol Chem 380: 431‐442, 1999.
 131.Ruszczak C, Mirza A, Menhart N. Differential stabilities of alternative exon‐skipped rod motifs of dystrophin. Biochim Biophys Acta 1794: 921‐928, 2009.
 132.Rybakova IN, Amann KJ, Ervasti JM. A new model for the interaction of dystrophin with F‐actin. J Cell Biol 135: 661‐672, 1996.
 133.Sadoulet‐Puccio HM, Rajala M, Kunkel LM. Dystrobrevin and dystrophin: An interaction through coiled‐coil motifs. Proc Natl Acad Sci U S A 94: 12413‐12418, 1997.
 134.Sandona D, Gastaldello S, Martinello T, Betto R. Characterization of the ATP‐hydrolysing activity of alpha‐sarcoglycan. Biochem J 381: 105‐112, 2004.
 135.Shi W, Chen Z, Schottenfeld J, Stahl RC, Kunkel LM, Chan YM. Specific assembly pathway of sarcoglycans is dependent on beta‐ and delta‐sarcoglycan. Muscle Nerve 29: 409‐419, 2004.
 136.Singh SM, Kongari N, Cabello‐Villegas J, Mallela KM. Missense mutations in dystrophin that trigger muscular dystrophy decrease protein stability and lead to cross‐beta aggregates. Proc Natl Acad Sci U S A 107: 15069‐15074, 2010.
 137.Sotgia F, Lee JK, Das K, Bedford M, Petrucci TC, Macioce P, Sargiacomo M, Bricarelli FD, Minetti C, Sudol M, Lisanti MP. Caveolin‐3 directly interacts with the C‐terminal tail of beta ‐dystroglycan. Identification of a central WW‐like domain within caveolin family members. J Biol Chem 275: 38048‐38058, 2000.
 138.Spence HJ, Dhillon AS, James M, Winder SJ. Dystroglycan, a scaffold for the ERK‐MAP kinase cascade. EMBO Rep 5: 484‐489, 2004.
 139.Stone MR, O'Neill A, Catino D, Bloch RJ. Specific interaction of the actin‐binding domain of dystrophin with intermediate filaments containing keratin 19. Mol Biol Cell 16: 4280‐4293, 2005.
 140.Stone MR, O'Neill A, Lovering RM, Strong J, Resneck WG, Reed PW, Toivola DM, Ursitti JA, Omary MB, Bloch RJ. Absence of keratin 19 in mice causes skeletal myopathy with mitochondrial and sarcolemmal reorganization. J Cell Sci 120: 3999‐4008, 2007.
 141.Stossel TP, Condeelis J, Cooley L, Hartwig JH, Noegel A, Schleicher M, Shapiro SS. Filamins as integrators of cell mechanics and signalling. Nat Rev Mol Cell Biol 2: 138‐145, 2001.
 142.Straub V, Duclos F, Venzke DP, Lee JC, Cutshall S, Leveille CJ, Campbell KP. Molecular pathogenesis of muscle degeneration in the delta‐sarcoglycan‐deficient hamster. Am J Pathol 153: 1623‐1630, 1998.
 143.Talts JF, Andac Z, Gohring W, Brancaccio A, Timpl R. Binding of the G domains of laminin alpha1 and alpha2 chains and perlecan to heparin, sulfatides, alpha‐dystroglycan and several extracellular matrix proteins. EMBO J 18: 863‐870, 1999.
 144.Thomas GD, Sander M, Lau KS, Huang PL, Stull JT, Victor RG. Impaired metabolic modulation of alpha‐adrenergic vasoconstriction in dystrophin‐deficient skeletal muscle. Proc Natl Acad Sci U S A 95: 15090‐15095, 1998.
 145.Thompson TG, Chan YM, Hack AA, Brosius M, Rajala M, Lidov HG, McNally EM, Watkins S, Kunkel LM. Filamin 2 (FLN2): A muscle‐specific sarcoglycan interacting protein. J Cell Biol 148: 115‐126, 2000.
 146.Tinsley J, Deconinck N, Fisher R, Kahn D, Phelps S, Gillis JM, Davies K. Expression of full‐length utrophin prevents muscular dystrophy in mdx mice. Nat Med 4: 1441‐1444, 1998.
 147.Tuffery‐Giraud S, Beroud C, Leturcq F, Yaou RB, Hamroun D, Michel‐Calemard L, Moizard MP, Bernard R, Cossee M, Boisseau P, Blayau M, Creveaux I, Guiochon‐Mantel A, de Martinville B, Philippe C, Monnier N, Bieth E, Khau Van Kien P, Desmet FO, Humbertclaude V, Kaplan JC, Chelly J, Claustres M. Genotype‐phenotype analysis in 2,405 patients with a dystrophinopathy using the UMD‐DMD database: A model of nationwide knowledgebase. Hum Mutat 30: 934‐945, 2009.
 148.Vainzof M, Takata RI, Passos‐Bueno MR, Pavanello RC, Zatz M. Is the maintainance of the C‐terminus domain of dystrophin enough to ensure a milder Becker muscular dystrophy phenotype? Hum Mol Genet 2: 39‐42, 1993.
 149.van den Bergen JC, Wokke BH, Janson AA, van Duinen SG, Hulsker MA, Ginjaar HB, van Deutekom JC, Aartsma‐Rus A, Kan HE, Verschuuren JJ. Dystrophin levels and clinical severity in Becker muscular dystrophy patients. J Neurol Neurosurg Psychiatry 85: 747‐753, 2014.
 150.van Putten M, Hulsker M, Young C, Nadarajah VD, Heemskerk H, van der Weerd L, t Hoen PA, van Ommen GJ, Aartsma‐Rus AM. Low dystrophin levels increase survival and improve muscle pathology and function in dystrophin/utrophin double‐knockout mice. FASEB J 27: 2484‐2495, 2013.
 151.Wagner KR, Cohen JB, Huganir RL. The 87K postsynaptic membrane protein from Torpedo is a protein‐tyrosine kinase substrate homologous to dystrophin. Neuron 10: 511‐522, 1993.
 152.Waite A, Brown SC, Blake DJ. The dystrophin‐glycoprotein complex in brain development and disease. Trends Neurosci 35: 487‐496, 2012.
 153.Way M, Pope B, Cross RA, Kendrick‐Jones J, Weeds AG. Expression of the N‐terminal domain of dystrophin in E. coli and demonstration of binding to F‐actin. FEBS Lett 301: 243‐245, 1992.
 154.Wein N, Vulin A, Falzarano MS, Szigyarto CA, Maiti B, Findlay A, Heller KN, Uhlen M, Bakthavachalu B, Messina S, Vita G, Passarelli C, Gualandi F, Wilton SD, Rodino‐Klapac LR, Yang L, Dunn DM, Schoenberg DR, Weiss RB, Howard MT, Ferlini A, Flanigan KM. Translation from a DMD exon 5 IRES results in a functional dystrophin isoform that attenuates dystrophinopathy in humans and mice. Nat Med 20: 992‐1000, 2014.
 155.Wheeler MT, Zarnegar S, McNally EM. Zeta‐sarcoglycan, a novel component of the sarcoglycan complex, is reduced in muscular dystrophy. Hum Mol Genet 11: 2147‐2154, 2002.
 156.Willer T, Amselgruber W, Deutzmann R, Strahl S. Characterization of POMT2, a novel member of the PMT protein O‐mannosyltransferase family specifically localized to the acrosome of mammalian spermatids. Glycobiology 12: 771‐783, 2002.
 157.Willer T, Lee H, Lommel M, Yoshida‐Moriguchi T, de Bernabe DB, Venzke D, Cirak S, Schachter H, Vajsar J, Voit T, Muntoni F, Loder AS, Dobyns WB, Winder TL, Strahl S, Mathews KD, Nelson SF, Moore SA, Campbell KP. ISPD loss‐of‐function mutations disrupt dystroglycan O‐mannosylation and cause Walker‐Warburg syndrome. Nat Genet 44: 575‐580, 2012.
 158.Williamson RA, Henry MD, Daniels KJ, Hrstka RF, Lee JC, Sunada Y, Ibraghimov‐Beskrovnaya O, Campbell KP. Dystroglycan is essential for early embryonic development: Disruption of Reichert's membrane in Dag1‐null mice. Hum Mol Genet 6: 831‐841, 1997.
 159.Yamanouchi K, Yada E, Ishiguro N, Hosoyama T, Nishihara M. Increased adipogenicity of cells from regenerating skeletal muscle. Exp Cell Res 312: 2701‐2711, 2006.
 160.Yang B, Jung D, Motto D, Meyer J, Koretzky G, Campbell KP. SH3 domain‐mediated interaction of dystroglycan and Grb2. J Biol Chem 270: 11711‐11714, 1995.
 161.Yoshida M, Hama H, Ishikawa‐Sakurai M, Imamura M, Mizuno Y, Araishi K, Wakabayashi‐Takai E, Noguchi S, Sasaoka T, Ozawa E. Biochemical evidence for association of dystrobrevin with the sarcoglycan‐sarcospan complex as a basis for understanding sarcoglycanopathy. Hum Mol Genet 9: 1033‐1040, 2000.
 162.Yoshida M, Suzuki A, Yamamoto H, Noguchi S, Mizuno Y, Ozawa E. Dissociation of the complex of dystrophin and its associated proteins into several unique groups by n‐octyl beta‐D‐glucoside. Eur J Biochem 222: 1055‐1061, 1994.
 163.Yoshida T, Pan Y, Hanada H, Iwata Y, Shigekawa M. Bidirectional signaling between sarcoglycans and the integrin adhesion system in cultured L6 myocytes. J Biol Chem 273: 1583‐1590, 1998.
 164.Yue Y, Liu M, Duan D. C‐terminal‐truncated microdystrophin recruits dystrobrevin and syntrophin to the dystrophin‐associated glycoprotein complex and reduces muscular dystrophy in symptomatic utrophin/dystrophin double‐knockout mice. Mol Ther 14: 79‐87, 2006.
 165.Zhang Y, Duan D. Novel mini‐dystrophin gene dual adeno‐associated virus vectors restore neuronal nitric oxide synthase expression at the sarcolemma. Hum Gene Ther 23: 98‐103, 2012.
 166.Zhu X, Hadhazy M, Groh ME, Wheeler MT, Wollmann R, McNally EM. Overexpression of gamma‐sarcoglycan induces severe muscular dystrophy. Implications for the regulation of Sarcoglycan assembly. J Biol Chem 276: 21785‐21790, 2001.
 167.Zimprich A, Grabowski M, Asmus F, Naumann M, Berg D, Bertram M, Scheidtmann K, Kern P, Winkelmann J, Muller‐Myhsok B, Riedel L, Bauer M, Muller T, Castro M, Meitinger T, Strom TM, Gasser T. Mutations in the gene encoding epsilon‐sarcoglycan cause myoclonus‐dystonia syndrome. Nat Genet 29: 66‐69, 2001.

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite

Quan Q. Gao, Elizabeth M. McNally. The Dystrophin Complex: Structure, Function, and Implications for Therapy. Compr Physiol 2015, 5: 1223-1239. doi: 10.1002/cphy.c140048