Dystrophin-Glycoprotein Complex: Post-translational Processing and Dystroglycan Function (2003)

dystrophin-glycoprotein complex neuronal nitric-oxide synthase Fukuyama congenital muscular dystrophy muscle-eye-brain disease Walker-Warburg Syndrome fukutin-related protein limb-girdle muscular dystrophy The dystrophin-glycoprotein complex (DGC)1 is a multimeric transmembrane protein complex first isolated from skeletal muscle membranes (1Ervasti J.M. Campbell K.P. Cell. 1991; 66: 1121-1131Abstract Full Text PDF PubMed Scopus (1119) Google Scholar). The central protein of the DGC is dystroglycan (Fig.1). In addition to skeletal muscle, dystroglycan is strongly expressed in heart and smooth muscle, as well as many non-muscle tissues including brain and peripheral nerve. In vertebrates, dystroglycan is generated from a single gene (DAG1), which is cleaved into a peripheral α-dystroglycan protein and a transmembrane β-dystroglycan protein (2Ibraghimov-Beskrovnaya O. Ervasti J.M. Leveille C.J. Slaughter C.A. Sernett S.W. Campbell K.P. Nature. 1992; 355: 696-702Crossref PubMed Scopus (1198) Google Scholar). At the sarcolemma in muscle, β-dystroglycan binds intracellularly to dystrophin, which binds the actin cytoskeleton, and extracellularly to α-dystroglycan. α-Dystroglycan completes the link from the cytoskeleton to the basal lamina by calcium-dependent binding with high affinity to extracellular matrix proteins (Fig. 1) containing LamG domains, such as laminin (3Ervasti J.M. Campbell K.P. J. Cell Biol. 1993; 122: 809-823Crossref PubMed Scopus (1185) Google Scholar), neurexin (4Sugita S. Saito F. Tang J. Satz J. Campbell K. Sudhof T.C. J. Cell Biol. 2001; 154: 435-445Crossref PubMed Scopus (375) Google Scholar), agrin (5Bowe M.A. Deyst K.A. Leszyk J.D. Fallon J.R. Neuron. 1994; 12: 1173-1180Abstract Full Text PDF PubMed Scopus (278) Google Scholar, 6Campanelli J.T. Roberds S.L. Campbell K.P. Scheller R.H. Cell. 1994; 77: 663-674Abstract Full Text PDF PubMed Scopus (340) Google Scholar, 7Gee S.H. Montanaro F. Lindenbaum M.H. Carbonetto S. Cell. 1994; 77: 675-686Abstract Full Text PDF PubMed Scopus (455) Google Scholar, 8Sugiyama J. Bowen D.C. Hall Z.W. Neuron. 1994; 13: 103-115Abstract Full Text PDF PubMed Scopus (237) Google Scholar), and perlecan (9Talts J.F. Andac Z. Gohring W. Brancaccio A. Timpl R. EMBO J. 1999; 18: 863-870Crossref PubMed Scopus (398) Google Scholar). In addition to dystroglycan and dystrophin, the DGC in muscle cells contains a sarcoglycan complex composed of four sarcoglycan proteins (α, β, γ, δ) and sarcospan (1Ervasti J.M. Campbell K.P. Cell. 1991; 66: 1121-1131Abstract Full Text PDF PubMed Scopus (1119) Google Scholar, 10Durbeej M. Cohn R.D. Hrstka R.F. Moore S.A. Allamand V. Davidson B.L. Williamson R.A. Campbell K.P. Mol. Cell. 2000; 5: 141-151Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar). Intracellularly, the sarcolemma DGC, through dystrophin, interacts with a pair of syntrophins (α1 and β1) (11Peters M.F. Adams M.E. Froehner S.C. J. Cell Biol. 1997; 138: 81-93Crossref PubMed Scopus (213) Google Scholar) and α-dystrobrevin (12Sadoulet-Puccio H.M. Rajala M. Kunkel L.M. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 12413-12418Crossref PubMed Scopus (167) Google Scholar). α-Syntrophin and α-dystrobrevin can interact with nNOS and localize it to the sarcolemma (13Kameya S. Miyagoe Y. Nonaka I. Ikemoto T. Endo M. Hanaoka K. Nabeshima Y. Takeda S. J. Biol. Chem. 1999; 274: 2193-2200Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar, 14Grady R.M. Grange R.W. Lau K.S. Maimone M.M. Nichol M.C. Stull J.T. Sanes J.R. Nat. Cell Biol. 1999; 1: 215-220Crossref PubMed Scopus (283) Google Scholar). Syntrophin also can interact with aquaporin 4 through a PDZ domain and can stabilize it in the sarcolemma (15Neely J.D. Amiry-Moghaddam M. Ottersen O.P. Froehner S.C. Agre P. Adams M.E. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 14108-14113Crossref PubMed Scopus (394) Google Scholar). The C-terminal tail of β-dystroglycan also contains a PPXY motif that can interact with dystrophin or caveolin 3 (16Sotgia F. Lee J.K. Das K. Bedford M. Petrucci T.C. Macioce P. Sargiacomo M. Bricarelli F.D. Minetti C. Sudol M. Lisanti M.P. J. Biol. Chem. 2000; 275: 38048-38058Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar). The exact function of the entire DGC is not completely determined but it is thought to contribute to the structural stability of the muscle cell membrane during cycles of contraction and relaxation (17Campbell K.P. Cell. 1995; 80: 675-679Abstract Full Text PDF PubMed Scopus (762) Google Scholar). In humans, mutations in dystrophin cause Duchenne and Becker muscular dystrophy, mutations in sarcoglycans in skeletal muscle cause limb-girdle muscular dystrophy, and mutations in α2 laminin cause congenital muscular dystrophy (18Cohn R.D. Campbell K.P. Muscle Nerve. 2000; 23: 1456-1471Crossref PubMed Scopus (426) Google Scholar). Despite the central role of dystroglycan in the DGC, no primary mutations in dystroglycan have been identified in any human disease. However, mutations in dystrophin do cause a secondary reduction in sarcolemma expression of dystroglycan (2Ibraghimov-Beskrovnaya O. Ervasti J.M. Leveille C.J. Slaughter C.A. Sernett S.W. Campbell K.P. Nature. 1992; 355: 696-702Crossref PubMed Scopus (1198) Google Scholar). Disruption of the DAG1 gene in mice results in embryonic lethality, and dystroglycan appears essential for the formation of the basement membrane (Reichert's membrane) that separates the embryo from the maternal circulation in the mouse (19Williamson R.A. Henry M.D. Daniels K.J. Hrstka R.F. Lee J.C. Sunada Y. Ibraghimov-Beskrovnaya O. Campbell K.P. Hum. Mol. Genet. 1997; 6: 831-841Crossref PubMed Scopus (450) Google Scholar, 20Henry M.D. Campbell K.P. Cell. 1998; 95: 859-870Abstract Full Text Full Text PDF PubMed Scopus (342) Google Scholar). Emerging genetic data have shown that mutations in proteins with homology to glycosyltransferases are linked to murine and human muscular dystrophies. Biochemical analysis of muscle biopsies has revealed a convergent role for these proteins in the glycosylation of α-dystroglycan, a process that is required for its functional activity. The loss of dystroglycan function by incomplete glycosylation can lead to a variety of clinical symptoms including muscular dystrophy and abnormal central nervous system development and function. Here we review what is known about the biosynthetic pathway of dystroglycan required for its normal structure and function and the new insights into dystroglycan function revealed from the study of mouse models and human patients with incomplete glycosylation-induced “dystroglycanopathies.” Because the only detected DGC defect in these “dystroglycanopathies” is the disruption of the dystroglycan ligand binding domain, the recent work supports the proposal that the functions of components of the DGC in the sarcolemma of differentiated skeletal muscle are largely to support the integrity and sarcolemma localization of the central extracellular matrix receptor, dystroglycan. An N-terminal signal peptide directs insertion of dystroglycan into the endoplasmic reticulum membrane with the N terminus in the lumen (Fig. 2 A). Dystroglycan is then cleaved by an unidentified protease at amino acid 653 into the α- and β-dystroglycan subunits (2Ibraghimov-Beskrovnaya O. Ervasti J.M. Leveille C.J. Slaughter C.A. Sernett S.W. Campbell K.P. Nature. 1992; 355: 696-702Crossref PubMed Scopus (1198) Google Scholar, 21Smalheiser N.R. Kim E. J. Biol. Chem. 1995; 270: 15425-15433Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar). The significance of this cleavage is unknown, particularly because the amino acid sequence around the cleavage site in vertebrate dystroglycan is not conserved inCaenorhabditis elegans and Drosophila melanogaster, and Western blotting with a C-terminal antibody suggests that the dystroglycan peptide is not cleaved into two subunits in Drosophila (22Deng W.M. Schneider M. Frock R. Castillejo-Lopez C. Gaman E.A. Baumgartner S. Ruohola-Baker H. Development. 2003; 130: 173-184Crossref PubMed Scopus (148) Google Scholar). N-Linked and fullO-linked glycosylation and plasma membrane trafficking of dystroglycan are not required for cleavage of dystroglycan, suggesting that it may occur in the endoplasmic reticulum (23Holt K.H. Crosbie R.H. Venzke D.P. Campbell K.P. FEBS Lett. 2000; 468: 79-83Crossref PubMed Scopus (153) Google Scholar, 24Michele D.E. Barresi R. Kanagawa M. Saito F. Cohn R.D. Satz J.S. Dollar J. Nishino I. Kelley R.I. Somer H. Straub V. Mathews K.D. Moore S.A. Campbell K.P. Nature. 2002; 418: 417-421Crossref PubMed Scopus (694) Google Scholar). The C-terminal region of α-dystroglycan (residues 550–585) binds to the N terminus of β-dystroglycan (residues 654–750) independently of glycosylation (25Sciandra F. Schneider M. Giardina B. Baumgartner S. Petrucci T.C. Brancaccio A. Eur. J. Biochem. 2001; 268: 4590-4597Crossref PubMed Scopus (38) Google Scholar). The sarcoglycan complex also appears to be required for a strong interaction of α-dystroglycan with the DGC in skeletal muscle. Sarcoglycan-null mutations, resulting in the loss of the sarcoglycan complex, result in dissociation of α-dystroglycan from muscle membranes and the DGC (10Durbeej M. Cohn R.D. Hrstka R.F. Moore S.A. Allamand V. Davidson B.L. Williamson R.A. Campbell K.P. Mol. Cell. 2000; 5: 141-151Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar). Dystroglycan undergoes N-linked and extensiveO-linked glycosylation, which causes α-dystroglycan to migrate on SDS-PAGE as a broad band with an approximate molecular mass of 120–180 kDa depending on tissue type (156 kDa in muscle, predicted molecular mass is ∼75 kDa) (2Ibraghimov-Beskrovnaya O. Ervasti J.M. Leveille C.J. Slaughter C.A. Sernett S.W. Campbell K.P. Nature. 1992; 355: 696-702Crossref PubMed Scopus (1198) Google Scholar). α-Dystroglycan contains a large mucin-like domain with a number of Ser or Thr residues, which are potential sites for O-glycosylation (2Ibraghimov-Beskrovnaya O. Ervasti J.M. Leveille C.J. Slaughter C.A. Sernett S.W. Campbell K.P. Nature. 1992; 355: 696-702Crossref PubMed Scopus (1198) Google Scholar). Dystroglycan also contains four potential N-linked glycosylation sites, three in α-dystroglycan and one in β-dystroglycan (2Ibraghimov-Beskrovnaya O. Ervasti J.M. Leveille C.J. Slaughter C.A. Sernett S.W. Campbell K.P. Nature. 1992; 355: 696-702Crossref PubMed Scopus (1198) Google Scholar). Exhaustive treatment of dystroglycan with N-glycanases does not alter its activity as an extracellular matrix receptor suggesting thatN-linked sugars are not required for ligand binding (3Ervasti J.M. Campbell K.P. J. Cell Biol. 1993; 122: 809-823Crossref PubMed Scopus (1185) Google Scholar). However, full chemical deglycosylation of dystroglycan results in the complete loss of ligand binding activity (3Ervasti J.M. Campbell K.P. J. Cell Biol. 1993; 122: 809-823Crossref PubMed Scopus (1185) Google Scholar). Interestingly, the same chemical deglycosylation also results in the loss of reactivity of two monoclonal antibodies raised against dystroglycan, clones IIH6 and VIA41 (3Ervasti J.M. Campbell K.P. J. Cell Biol. 1993; 122: 809-823Crossref PubMed Scopus (1185) Google Scholar). IIH6 antibody inhibits laminin binding, suggesting thatO-linked sugars are required for both ligand binding and the reaction of these monoclonal antibodies with dystroglycan (3Ervasti J.M. Campbell K.P. J. Cell Biol. 1993; 122: 809-823Crossref PubMed Scopus (1185) Google Scholar). TheO-linked glycoconjugates contain a fairly unique sugar linkage where mannose is directly coupled to serine or threonine in the dystroglycan peptide (26Chiba A. Matsumura K. Yamada H. Inazu T. Shimizu T. Kusunoki S. Kanazawa I. Kobata A. Endo T. J. Biol. Chem. 1997; 272: 2156-2162Abstract Full Text Full Text PDF PubMed Scopus (381) Google Scholar, 27Smalheiser N.R. Haslam S.M. Sutton-Smith M. Morris H.R. Dell A. J. Biol. Chem. 1998; 273: 23698-23703Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar). This O-mannosyl linkage has only been found in a few other mammalian proteins (28Endo T. Biochim. Biophys. Acta. 1999; 1473: 237-246Crossref PubMed Scopus (127) Google Scholar). In peripheral nerve dystroglycan, this Neu5Ac(α2–3)Gal(β1–4)GlcNAc(β1–2)Man-Ser/Thr glycoconjugate has been proposed to be required for laminin binding (26Chiba A. Matsumura K. Yamada H. Inazu T. Shimizu T. Kusunoki S. Kanazawa I. Kobata A. Endo T. J. Biol. Chem. 1997; 272: 2156-2162Abstract Full Text Full Text PDF PubMed Scopus (381) Google Scholar). However, millimolar concentrations of this glycoconjugate are required to competitively inhibit laminin binding to dystroglycan (26Chiba A. Matsumura K. Yamada H. Inazu T. Shimizu T. Kusunoki S. Kanazawa I. Kobata A. Endo T. J. Biol. Chem. 1997; 272: 2156-2162Abstract Full Text Full Text PDF PubMed Scopus (381) Google Scholar). Sialic acid has also been reported to competitively inhibit laminin binding to peripheral nerve dystroglycan at lower concentrations than the above glycoconjugate (29Yamada H. Chiba A. Endo T. Kobata A. Anderson L.V. Hori H. Fukuta-Ohi H. Kanazawa I. Campbell K.P. Shimizu T. Matsumura K. J. Neurochem. 1996; 66: 1518-1524Crossref PubMed Scopus (100) Google Scholar). However, enzymatic removal of sialic acid from skeletal muscle dystroglycan has no effect on laminin binding (30Ervasti J.M. Burwell A.L. Geissler A.L. J. Biol. Chem. 1997; 272: 22315-22321Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar). Furthermore, dystroglycan from brain and cardiac muscle has decreased terminal sialoglycosylation compared with skeletal muscle dystroglycan, but dystroglycan from all three tissues binds tightly to laminin (30Ervasti J.M. Burwell A.L. Geissler A.L. J. Biol. Chem. 1997; 272: 22315-22321Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar). Therefore, although it is well accepted that glycoconjugates are indeed important for ligand binding, the hypothesis that specific glycoconjugates on dystroglycan are involved directly in ligand binding is still controversial. The extensive glycosylation of dystroglycan has made the elucidation of the structure of the peptide and glycoconjugates and the generation of peptide antibodies technically challenging. Rotary and of α-dystroglycan with two linked by a A. T. M. J. FEBS Lett. 1995; PubMed Scopus Google Scholar). the domain to the domain by the large number of The structure of the terminus of dystrophin with a β-dystroglycan peptide has revealed that an domain in dystrophin an interaction of a motif in the C-terminal tail of β-dystroglycan with a domain in dystrophin F. R. A. Sudol M. Nat. Biol. 2000; PubMed Scopus Google Scholar). The structure of the α2 laminin that a is by a that is thought to the site for with acid glycoconjugates as sialic on dystroglycan J.F. Timpl R. E. 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However, recent data in and muscle that α-dystroglycan protein and the entire DGC are at the but α-dystroglycan is in molecular mass by kDa D.E. Barresi R. Kanagawa M. Saito F. Cohn R.D. Satz J.S. Dollar J. Nishino I. Kelley R.I. Somer H. Straub V. Mathews K.D. Moore S.A. Campbell K.P. Nature. 2002; 418: 417-421Crossref PubMed Scopus (694) Google Scholar). The of α-dystroglycan results in the of for the monoclonal IIH6 and to the chemical deglycosylation by Ervasti and Campbell (3Ervasti J.M. Campbell K.P. J. Cell Biol. 1993; 122: 809-823Crossref PubMed Scopus (1185) Google Scholar). also on of mutations in in the patients D.E. Barresi R. Kanagawa M. Saito F. Cohn R.D. Satz J.S. Dollar J. Nishino I. Kelley R.I. Somer H. Straub V. Mathews K.D. Moore S.A. Campbell K.P. Nature. 2002; 418: 417-421Crossref PubMed Scopus (694) Google Scholar), this can be to abnormal O-mannosyl glycosylation of α-dystroglycan. This causes α-dystroglycan to be as a receptor for its known extracellular matrix including and agrin D.E. Barresi R. Kanagawa M. Saito F. Cohn R.D. Satz J.S. Dollar J. Nishino I. Kelley R.I. Somer H. Straub V. Mathews K.D. Moore S.A. Campbell K.P. Nature. 2002; 418: 417-421Crossref PubMed Scopus (694) Google Scholar). Interestingly, sarcolemma by also both normal and revealed an complete loss of high affinity laminin binding suggesting that dystroglycan is one of the laminin in human muscle sarcolemma D.E. Barresi R. Kanagawa M. Saito F. Cohn R.D. Satz J.S. Dollar J. Nishino I. Kelley R.I. Somer H. Straub V. Mathews K.D. Moore S.A. Campbell K.P. Nature. 2002; 418: 417-421Crossref PubMed Scopus (694) Google Scholar). Because mutations in laminin α2 A. H. C. F. J. K. M. K. P. Nat. Genet. 1995; PubMed Scopus Google Scholar) and dystrophin R.H. Kunkel L.M. Cell. Full Text PDF PubMed Scopus Google Scholar) also cause muscular dystrophy, the muscle is to a loss of the functional link the sarcolemma by dystroglycan from dystrophin to However, a dystroglycan for the neuronal in human in the mouse identified by in the gene which also a Nat. Genet. 2001; PubMed Scopus Google Scholar). Despite than the of the no brain been T.C. J. PubMed Scopus Google Scholar). of the of the mice revealed abnormal glycosylation of α-dystroglycan to the functional loss of ligand binding activity to skeletal muscle, abnormal human and in cell D.E. Barresi R. Kanagawa M. Saito F. Cohn R.D. Satz J.S. Dollar J. Nishino I. Kelley R.I. Somer H. Straub V. Mathews K.D. Moore S.A. Campbell K.P. Nature. 2002; 418: 417-421Crossref PubMed Scopus (694) Google Scholar). Because a number of proteins be by this enzymatic it still the functional defect in α-dystroglycan to for the brain gene the dystroglycan gene in the mouse and the abnormal neuronal the mouse and in and patients S.A. Saito F. J. D.E. Henry M.D. A. Cohn R.D. S. Williamson R.A. T. Campbell K.P. Nature. 2002; 418: PubMed Scopus Google Scholar). The recent of the human gene as a and the loss of α-dystroglycan in muscle biopsies S. A. J. E. B. H. B. J. T. C.A. H. J. Hum. Genet. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar) suggests that and and brain can be by a loss of function of α-dystroglycan to abnormal not all the in this α-dystroglycan pathway have been and mutations in these may be for of muscular dystrophy and of abnormal neuronal (Fig. 2 In patients with mutations, no brain is M. Y. P. S.C. S. M.A. R. Anderson L.V. R. J.M. S. M. Straub V. C. I. C.A. K. T. F. Hum. Mol. Genet. 2001; PubMed Google Scholar, M. P. S.C. S. M.A. B. E. T. C.A. P. F. J. Hum. Genet. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar) suggesting that for activity in This also the that involved in dystroglycan in brain may be for of human muscular The in and in the suggests may be or for these in the In the recent on only of patients mutations in suggesting that unidentified may be required for dystroglycan glycosylation in these patients S. A. J. E. B. H. B. J. T. C.A. H. J. Hum. Genet. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). mice also the embryonic in dystroglycan mice suggesting a potential for gene is a of A. J. 1999; PubMed Scopus Google Scholar). in E. A. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google Scholar), although it has not been that this is by a defect in the and enzymatic of and have not been mutations in cause a molecular mass kDa) of α-dystroglycan as in patients D.E. Barresi R. Kanagawa M. Saito F. Cohn R.D. Satz J.S. Dollar J. Nishino I. Kelley R.I. Somer H. Straub V. Mathews K.D. Moore S.A. Campbell K.P. Nature. 2002; 418: 417-421Crossref PubMed Scopus (694) Google Scholar). This suggests that and may interact with or by sugars or directly enzymatic activity The of α-dystroglycan in human patients and mouse models have revealed important new insights into the function of dystroglycan and the the genetic role of the DGC in muscular dystrophy is well the functional role of dystroglycan in skeletal muscle is still Because dystroglycan is important for of membrane in (19Williamson R.A. Henry M.D. Daniels K.J. Hrstka R.F. Lee J.C. Sunada Y. Ibraghimov-Beskrovnaya O. Campbell K.P. Hum. Mol. Genet. 1997; 6: 831-841Crossref PubMed Scopus (450) Google Scholar, 20Henry M.D. Campbell K.P. Cell. 1998; 95: 859-870Abstract Full Text Full Text PDF PubMed Scopus (342) Google Scholar), it that skeletal muscle basement membranes be dystroglycan or However, large of basement membrane and matrix protein expression in mouse the skeletal muscle basement membranes in mice are with normal matrix protein expression and localization D.E. Barresi R. Kanagawa M. Saito F. Cohn R.D. Satz J.S. Dollar J. Nishino I. Kelley R.I. Somer H. Straub V. Mathews K.D. Moore S.A. Campbell K.P. Nature. 2002; 418: 417-421Crossref PubMed Scopus (694) Google Scholar). Muscle basement membrane formation is also normal the dystroglycan gene is in muscle R.D. Henry M.D. D.E. Barresi R. Saito F. Moore S.A. J.D. M.E. J.R. Williamson R.A. Campbell K.P. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). This suggests that dystroglycan may not be essential as a basement membrane in muscle, and matrix may for the functional loss of dystroglycan. containing are also required in with dystroglycan for complete embryonic basement membrane M.D. Satz J.S. C. M. E. R. Campbell K.P. J. Cell Sci. 2001; PubMed Google Scholar, S. Carbonetto S. R. J. Cell Biol. 2002; PubMed Scopus Google Scholar, R. M. 1995; PubMed Scopus Google Scholar) and may in for the loss of dystroglycan as a basement membrane in muscle H. J. Cell Biol. 1999; PubMed Scopus Google Scholar, K.J. J. Cell Biol. 2001; PubMed Scopus Google Scholar). The function of dystroglycan in muscle has also been by specific genetic of the DAG1 gene in mice generated from embryonic cells that the genetic reduction of dystroglycan expression in muscle cause muscular dystrophy H. Lindenbaum M. Carbonetto S. Nat. Genet. 1999; 23: PubMed Scopus Google Scholar). to muscle basement membrane formation normal in mice H. Lindenbaum M. Carbonetto S. Nat. Genet. 1999; 23: PubMed Scopus Google Scholar). In although dystroglycan may still an important role as an agrin receptor in the development of the dystroglycan expression is not required for formation of this sarcolemma in to agrin R.M. H. J.M. Henry M.D. Campbell K.P. Sanes J.R. Neuron. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, C. Carbonetto S. J. Cell Biol. 2001; PubMed Scopus Google Scholar). the DAG1 gene by in differentiated skeletal muscle and in normal muscle basement membrane formation but a R.D. Henry M.D. D.E. Barresi R. Saito F. Moore S.A. J.D. M.E. J.R. Williamson R.A. Campbell K.P. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). The to in these to dystroglycan expressed in and mice a to to muscle compared with other mouse models R.D. Henry M.D. D.E. Barresi R. Saito F. Moore S.A. J.D. M.E. J.R. Williamson R.A. Campbell K.P. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). This suggests that dystroglycan may an important role in cell or function. Interestingly, muscle biopsies from human patients with a dystroglycan defect and limb-girdle muscular dystrophy also although not determined in this patients a expression of dystroglycan from cells R.D. Henry M.D. D.E. Barresi R. Saito F. Moore S.A. J.D. M.E. J.R. Williamson R.A. Campbell K.P. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). This be by an that for the in these but the expression of the as the during the This of normal dystroglycan expression from cells is not in the muscular of mice and or patients D.E. Barresi R. Kanagawa M. Saito F. Cohn R.D. Satz J.S. Dollar J. Nishino I. Kelley R.I. Somer H. Straub V. Mathews K.D. Moore S.A. Campbell K.P. Nature. 2002; 418: 417-421Crossref PubMed Scopus (694) Google Scholar). Therefore, of the dystroglycan pathway and its may important into dystroglycan cell function and dystroglycan be to functional dystroglycan muscle and the Despite the loss of laminin binding activity of dystroglycan and muscle, the DGC proteins can still localize to the sarcolemma D.E. Barresi R. Kanagawa M. Saito F. Cohn R.D. Satz J.S. Dollar J. Nishino I. Kelley R.I. Somer H. Straub V. Mathews K.D. Moore S.A. Campbell K.P. Nature. 2002; 418: 417-421Crossref PubMed Scopus (694) Google Scholar). dystrophin and proteins can still localize to the sarcolemma the genetic of the entire dystroglycan protein in muscle R.D. Henry M.D. D.E. Barresi R. Saito F. Moore S.A. J.D. M.E. J.R. Williamson R.A. Campbell K.P. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, H. Carbonetto S. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). 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