Identification of Dp71 Isoforms in the Platelet Membrane Cytoskeleton

Utrophin is a component of the platelet membrane cytoskeleton and participates in cytoskeletal reorganization (Earnest, J. P., Santos, G. F., Zuerbig, S., and Fox, J. E. B. (1995) J. Biol. Chem. 270, 27259–27265). Although platelets do not contain dystrophin, the identification of smaller C-terminal isoforms of dystrophin, including Dp71, which are expressed in a wide range of nonmuscle tissues and cell lines, has not been investigated. In this report, we have identified Dp71 protein variants of 55–60 kDa (designated Dp71Δ110) in the membrane cytoskeleton of human platelets. Both Dp71Δ110and utrophin sediment from lysed platelets along with the high speed detergent-insoluble pellet, which contains components of the membrane cytoskeleton. Like the membrane cytoskeletal proteins vinculin and spectrin, Dp71Δ110 and utrophin redistributed from the high speed detergent-insoluble pellet to the integrin-rich low speed pellet of thrombin-stimulated platelets. Immunoelectron microscopy provided further evidence that Dp71Δ110 was localized to the submembranous cytoskeleton. In addition to Dp71Δ110, platelets contained several components of the dystrophin-associated protein complex, including β-dystroglycan and syntrophin. To better understand the potential function of Dp71Δ110, collagen adhesion assays were performed on platelets isolated from wild-type or Dp71-deficient (mdx3cv) mice. Adhesion to collagen in response to thrombin was significantly decreased in platelets isolated from mdx3cv mice, compared with wild-type platelets. Collectively, our results provide evidence that Dp71Δ110is a component of the platelet membrane cytoskeleton, is involved in cytoskeletal reorganization and/or signaling, and plays a role in thrombin-mediated platelet adhesion. Utrophin is a component of the platelet membrane cytoskeleton and participates in cytoskeletal reorganization (Earnest, J. P., Santos, G. F., Zuerbig, S., and Fox, J. E. B. (1995) J. Biol. Chem. 270, 27259–27265). Although platelets do not contain dystrophin, the identification of smaller C-terminal isoforms of dystrophin, including Dp71, which are expressed in a wide range of nonmuscle tissues and cell lines, has not been investigated. In this report, we have identified Dp71 protein variants of 55–60 kDa (designated Dp71Δ110) in the membrane cytoskeleton of human platelets. Both Dp71Δ110and utrophin sediment from lysed platelets along with the high speed detergent-insoluble pellet, which contains components of the membrane cytoskeleton. Like the membrane cytoskeletal proteins vinculin and spectrin, Dp71Δ110 and utrophin redistributed from the high speed detergent-insoluble pellet to the integrin-rich low speed pellet of thrombin-stimulated platelets. Immunoelectron microscopy provided further evidence that Dp71Δ110 was localized to the submembranous cytoskeleton. In addition to Dp71Δ110, platelets contained several components of the dystrophin-associated protein complex, including β-dystroglycan and syntrophin. To better understand the potential function of Dp71Δ110, collagen adhesion assays were performed on platelets isolated from wild-type or Dp71-deficient (mdx3cv) mice. Adhesion to collagen in response to thrombin was significantly decreased in platelets isolated from mdx3cv mice, compared with wild-type platelets. Collectively, our results provide evidence that Dp71Δ110is a component of the platelet membrane cytoskeleton, is involved in cytoskeletal reorganization and/or signaling, and plays a role in thrombin-mediated platelet adhesion. Duchenne muscular dystrophy (DMD) 1The abbreviations used are: DMD, Duchenne muscular dystrophy; DAPC, dystrophin-associated protein complex; Dp71Δ110, 55- to 60-kDa variant of Dp71; Dp71Δ110m, Dp71Δ110 containing the C-terminal sequences of muscle dystrophin; Dp71Δ110a, Dp71Δ110 containing the alternative 31-amino acid C-terminal sequence due to the splicing of exon 78; PBS, phosphate-buffered saline; HRP, horseradish peroxidase; BSA, bovine serum albumin; RFU, relative fluorescence units is an X-linked recessive disease characterized by progressive degeneration of muscle resulting in early death from respiratory or cardiac failure (1Burton E.A. Davies K.E. Cell. 2002; 108: 5-8Google Scholar, 2Blake D.J. Weir A. Newey S.E. Davies K.E. Physiol. Rev. 2002; 82: 291-329Google Scholar). DMD is caused by mutations in the dystrophin gene, leading to the loss of dystrophin, a 427-kDa membrane-associated cytoskeletal protein. Analysis of dystrophin expression has led to the identification of several tissue-specific and/or developmentally regulated C-terminal dystrophin isoforms generated through differential promoter usage and/or alternative splicing at the 3′-end of the gene (3Feener C.A. Koenig M. Kunkel L.M. Nature. 1989; 338: 509-511Google Scholar, 4Chelly J. Gilgenkrantz H. Lanbert M. Hamard G. Chafey P. Katz P. de la Chapelle A. Koenig M. Ginjaar I. Fardeau M. Tome F. Kahn A. Kaplan J.C. Cell. 1990; 63: 1239-1248Google Scholar, 5Pillers D.-A.M. Bulman D.E. Weleber R.G. Sigesmond D.A. Musarella M.A. Powell B.R. Murphey W.H. Westall C. Panton C. Becker L.E. Worton R.G. Ray P.N. Nat. Genet. 1993; 4: 82-86Google Scholar, 6Bies R.D. Phelps S.F. Cortez M.D. Roberts R. Caskey C.T. Chamberlain J.S. Nucleic Acids Res. 1992; 20: 1725-1731Google Scholar, 7Dickson G. Pizzey J.A. Elsom V.E. Love D. Davies K.E. Walsh F.C. FEBS Lett. 1988; 242: 47-52Google Scholar). Dp71, a dystrophin protein of 70–75 kDa, is the major dystrophin gene product found in a wide range of nonmuscle tissues (8Austin R.C. Howard P.L. D'Souza V.N. Ray P.N. Hum. Mol. Genet. 1995; 4: 1475-1483Google Scholar, 9Hugnot J.P. Gilgenkrantz H. Vincent N. Chafey P. Morris G.E. Monaco A.P. Berwal-Netter Y. Koulakoff A. Kaplan J.C. Kahn A. Chelly J. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 7506-7510Google Scholar, 10Lederfein D. Levy Z. Augier N. Mornet D. Morris G. Fuchs O. Yaffe D. Nudel U. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 5346-5350Google Scholar, 11Rapaport D. Greenberg D.S. Tal M. Yaffe D. Nudel U. FEBS Lett. 1993; 328: 197-202Google Scholar, 12Blake D.J. Love D.R. Tinsley J.M. Morris G.E. Turley H. Gatter K. Dickson G. Edwards Y.H. Davies K.E. Hum. Mol. Genet. 1992; 1: 103-109Google Scholar, 13Bar S. Barnea E. Levy Z. Neuman S. Yaffe D. Nudel U. Biochem. J. 1990; 272: 557-560Google Scholar). The Dp71 transcript, which is regulated by a promoter situated between exons 62 and 63 of the dystrophin gene, encodes the cysteine-rich and C-terminal domains of dystrophin. Because Dp71 transcripts are alternatively spliced for exons 71 and/or 78 in a wide range of nonmuscle tissues, multiple Dp71 protein products of 70–75 kDa are generated, all of which can be identified using dystrophin-specific antibodies directed against the C terminus of the protein (8Austin R.C. Howard P.L. D'Souza V.N. Ray P.N. Hum. Mol. Genet. 1995; 4: 1475-1483Google Scholar). In addition to these Dp71 isoforms, we have recently identified a subpopulation of Dp71 transcripts in human brain that do not contain exons 71–74 and are alternatively spliced for exon 78 (14). Consistent with the expected translation of these Dp71 transcripts, immunoblot analysis using dystrophin-specific C-terminal antibodies detected an immunoreactive protein of ∼58 kDa (designated Dp71Δ110) in total protein lysates from adult human brain. The observation that Dp71Δ110 fails to react with a monoclonal antibody (MANEX7374A) directed against epitopes within exons 73 and 74 provides further evidence that Dp71Δ110 is derived from Dp71 transcripts lacking exons 71–74. Other C-terminal isoforms of dystrophin have been identified in the retina (Dp260) (15D'Souza V.N. Man N.T. Morris G.E. Karges W. Pillers D.M. Ray P.N. Hum. Mol. Genet. 1995; 4: 837-842Google Scholar) and in the peripheral (Dp116) (16Byers T.J. Lidov H.G.W. Kunkel L.M. Nat. Genet. 1993; 4: 77-81Google Scholar) and central nervous systems (Dp140) (17Lidov H.G.W. Selig S. Kunkel L.M. Hum. Mol. Genet. 1995; 4: 329-335Google Scholar). In addition, the autosomal homologue of dystrophin (18Love D.R. Hill D.F. Dickson G. Spurr N.K. Byth B.C. Marsden R.F. Walsh F.S. Edwards Y.H. Davies K.E. Nature. 1989; 339: 55-58Google Scholar), utrophin, is expressed in a wide range of nonmuscle tissues and cell lines (19Man N.T. Thanh L.T. Blake D.J. Davies K.E. Morris G.E. FEBS Lett. 1992; 313: 19-22Google Scholar, 20Matsumura K. Shasby D.M. Campbell K.P. FEBS Lett. 1993; 326: 289-293Google Scholar). Although there is considerable information regarding the tissue distribution and structure of these C-terminal dystrophin isoforms, relatively little is known about their function. Dp71 associates with components of the dystrophin-associated protein complex (DAPC) (21Cox G.A. Sunada Y. Campbell K.P. Chamberlain J.S. Nat. Genet. 1994; 8: 333-339Google Scholar, 22Greenberg D.S. Sunada Y. Campbell K.P. Yaffe D. Nudel U. Nat. Genet. 1994; 8: 340-344Google Scholar) and localizes to the plasma membrane (23Jung D. Filliol D. Metz-Boutigue M.-H. Rendon A. Neuromusc. Disord. 1993; 3: 515-518Google Scholar), raising the possibility that Dp71 plays a role in the formation and/or stabilization of the membrane cytoskeleton. This concept is further supported by studies showing that mice deficient in Dp71 have reduced levels of the DAPC in their brain (24Greenberg D.S. Schatz Y. Levy Z. Pizzo P. Yaffe D. Nudel U. Hum. Mol. Genet. 1996; 5: 1299-1303Google Scholar). However, direct evidence that Dp71 is a component of the membrane cytoskeleton or that it is involved in cytoskeletal reorganization and/or transmembrane is is that platelets contain a complex membrane cytoskeleton that at in the cytoskeleton found in muscle J. and J. B. Scholar, E.A. U. G.A. Biochem. J. Scholar). studies have identified utrophin a component of the platelet membrane cytoskeleton and that it participates in cytoskeletal reorganization platelet J.P. S. J. Biol. Chem. 1995; Scholar). Although platelets do not contain dystrophin, the of C-terminal dystrophin isoforms was not In the we provide evidence that Dp71Δ110 is expressed in human is a component of the platelet membrane cytoskeleton, and in reorganization of the cytoskeleton platelet In of platelet adhesion to collagen in response to thrombin was significantly reduced in platelets from Dp71-deficient (mdx3cv) mice, compared with platelets from wild-type mice. results that Dp71Δ110 plays a potential role in thrombin-stimulated platelet by cytoskeletal reorganization and/or were from the and in with bovine and were at in a of the antibodies used in this and the against which are The and of the dystrophin-specific C-terminal antibody have been Bulman D.E. G. B. J. Ray P.N. Worton R.G. Nature. 1988; Scholar). The antibody which is directed against the alternative 31-amino acid C terminus of dystrophin, has been (8Austin R.C. Howard P.L. D'Souza V.N. Ray P.N. Hum. Mol. Genet. 1995; 4: 1475-1483Google Scholar). is a monoclonal antibody directed against epitopes within exons 73 and 74 of dystrophin and Dp71 R.C. Morris G.E. Howard P.L. Ray P.N. Neuromusc. Disord. Scholar, G.E. C. Biochem. Res. 1995; Scholar). is a monoclonal antibody directed against the central of dystrophin that not with utrophin N.T. Morris G.E. Love D.R. Davies K.E. FEBS Lett. 1990; Scholar). is a monoclonal antibody directed against utrophin that not with dystrophin N.T. J.M. Love D.R. Davies K.E. Gatter Dickson G. Morris G.E. J. Biol. Scholar). antibodies directed against β-dystroglycan Walsh J. 1994; Scholar) or were from antibodies against were from antibodies against vinculin or were from antibodies were against M. R. J. Biol. Scholar). The and of the has been P.L. R.C. Worton R.G. Ray P.N. used in this and their antibody and monoclonal antibody of of muscle dystrophin and C-terminal of muscle dystrophin and of muscle of exons 73 and 74 of of of of of human antibody and monoclonal antibody in a was from of The was at for at and the plasma was and to an isolated in this were to be using a cell platelet platelets were by at for at in containing of and at a of in and were by addition of provided by of platelet lysates were by the addition of an of by at at for to pellet The was at for at to pellet components of the membrane cytoskeleton J. Biol. 1988; Scholar). components were to immunoblot from human platelets using the was at in of platelet was used to using a to a sequence in the of the human sequence or (8Austin R.C. Howard P.L. D'Souza V.N. Ray P.N. Hum. Mol. Genet. 1995; 4: 1475-1483Google Scholar). The used to exon 78 of the dystrophin were and for analysis using and for were at the for and in a of containing of the of units of in a of and of were to in a with a of of for for and for products were on a containing protein lysates from human or were in to for and on and Nature. Scholar). were from to and (8Austin R.C. Howard P.L. D'Souza V.N. Ray P.N. Hum. Mol. Genet. 1995; 4: 1475-1483Google Scholar). with the and horseradish were using the were from or platelets were and by for at in in containing platelets were to to for at several with PBS, by containing bovine serum and to were with containing BSA, and with the dystrophin-specific C-terminal antibody for at a were with in of with containing BSA, were with a to for at were with containing and with in in a of were with a of and in a using platelet were with the antibody with PBS, and with a for at several with PBS, the were for in a of in containing platelets were in in an of and in with with a were in a mice were from mdx3cv mice were from was from the of wild-type or mdx3cv mice of and in containing plasma was by of the at for at through a an plasma was in containing platelets were by at for and at in containing and or containing in was to the of at a of in a were with were and for at with containing to the platelets were for with in containing The of platelet was using a by the fluorescence for at at The results are relative fluorescence units platelets and the S.E. of using platelets isolated from wild-type or mdx3cv mice. are the S.E. of between wild-type and mdx3cv platelets were by analysis of were were all of were To human platelets contain dystrophin, C-terminal isoforms of dystrophin and/or utrophin, total platelet lysates were on and to immunoblot with a dystrophin-specific antibody directed against the C-terminal of muscle dystrophin, dystrophin was in muscle not in DMD muscle or platelets However, platelets contained an immunoreactive protein that at an of 55–60 kDa (designated and not proteins of (designated were identified using an antibody directed against the alternative 31-amino acid C terminus of dystrophin that results from alternative splicing of exon 78 or an antibody for the acid terminus of Dp71 The observation that a monoclonal antibody (MANEX7374A) directed against epitopes within exons 73 and 74 to these proteins not that are derived from Dp71 transcripts for exons 71–74. a monoclonal antibody directed against the of dystrophin not react with these platelet proteins react with muscle dystrophin Consistent with our J.P. S. J. Biol. Chem. 1995; Scholar), utrophin was identified in platelets using a monoclonal antibody against the C-terminal of utrophin The and of utrophin in platelets were to that of utrophin found in DMD muscle and The observation that utrophin levels in DMD muscle are compared with is with K. J.M. K. Campbell K.P. Nature. 1992; Scholar, G. S. Morris G.E. Davies K.E. C. P. J. 1993; Scholar). for Dp71Δ110 in adult human brain R.C. Morris G.E. Howard P.L. Ray P.N. Neuromusc. Disord. Scholar), of the of Dp71 in adult human platelets in the expected product not To that platelet proteins detected by the dystrophin-specific C-terminal antibodies and were derived from Dp71Δ110 transcripts alternatively spliced for exon platelet was by using exon 78 a was generated from Dp71 containing an exon 78 platelet was used the products of and were generated of that the contained an exon the was for exon 78 not a of platelet in the in a loss of these products the and products generated from platelet from alternative splicing of the exon 78 and provides further evidence that platelet Dp71Δ110 is alternatively spliced for exon Because platelets are derived from we the expression of Dp71Δ110, dystrophin, and utrophin in a cell that of the and of D.S. R. 1988; Scholar). protein lysates from and were to immunoblot analysis using antibodies for the C terminus of dystrophin or utrophin in containing the C-terminal sequence of muscle dystrophin was found in platelets and However, compared with containing the alternative 31-amino acid C-terminal sequence was not detected in Dp71Δ110 is derived from Dp71 transcripts that exon In of analysis of cell the of Dp71Δ110 transcripts containing exon 78 not in there was evidence of Dp71Δ110 in muscle and do not contain dystrophin utrophin studies have that dystrophin and C-terminal isoforms are with the membrane cytoskeleton in muscle and nonmuscle tissues (21Cox G.A. Sunada Y. Campbell K.P. Chamberlain J.S. Nat. Genet. 1994; 8: 333-339Google Scholar, 22Greenberg D.S. Sunada Y. Campbell K.P. Yaffe D. Nudel U. Nat. Genet. 1994; 8: 340-344Google Scholar, D.R. Morris G.E. J.M. U. Marsden R.F. Walsh F.S. Edwards Y.H. D.J. Davies K.E. Proc. Natl. Acad. Sci. U. S. A. Scholar, J.M. Campbell K.P. Cell. Scholar, J.M. Campbell K.P. J. Biol. 1993; Scholar). To Dp71Δ110 associates with the platelet membrane cytoskeleton, platelets were lysed with a and the cytoskeletal components were isolated by differential with total platelet lysates the components of the platelet cytoskeleton, including were by at speed pellet, the detergent-insoluble membrane cytoskeleton was by of the at speed pellet, containing the C-terminal sequence of muscle dystrophin was in the detergent-insoluble In of the alternative 31-amino acid C-terminal sequence were in the detergent-insoluble and and Consistent with our J.P. S. J. Biol. Chem. 1995; Scholar), utrophin was in the detergent-insoluble with a in the that Dp71Δ110, utrophin, is a component of the membrane cytoskeleton. studies have that the platelet cytoskeleton reorganization platelets are that and cytoskeletal proteins sediment at low from platelets 1993; E.A. J.S. J. Biol. Chem. 1993; Scholar). In addition, is from and on platelets resulting in platelet a reorganization of the cytoskeleton that membrane cytoskeletal proteins and high to be from platelets and can be at low in Dp71Δ110 containing the C-terminal sequence of dystrophin or the alternative 31-amino acid C-terminal sequence sediment at low platelets were with This was with In addition, the at which Dp71Δ110 and utrophin redistributed to the low speed pellet with that of vinculin and spectrin, known platelet membrane cytoskeletal that Dp71Δ110 and utrophin are of the membrane cytoskeleton that is integrin-rich cytoskeletal platelet performed on human Dp71Δ110 to the plasma with the localized to of the plasma membrane was in the microscopy Dp71Δ110 localized to the plasma membrane of platelets and at the membrane from the In there was of the plasma membrane in To human platelets contain components of the DAPC J.M. Blake D.J. Davies K.E. Proc. Natl. Acad. Sci. U. S. A. 1994; Scholar), total platelet proteins were to immunoblot analysis using antibodies to of the or complex In to human platelets not contain or the muscle isoforms of and However, platelets were to contain β-dystroglycan and studies have that with dystrophin, utrophin, and multiple of Dp71 in a wide range of tissues C.A. E. M. E. Kunkel L.M. J. Biol. Chem. 1996; Scholar, A. R. J. Biol. Chem. 1994; Scholar). that platelets contain utrophin, Dp71Δ110, and the of was in platelets. for utrophin and Dp71Δ110, at low platelets were with thrombin of was in platelet in which cell and were not a with utrophin, and J.P. S. J. Biol. Chem. 1995; Scholar, E.A. J.S. J. Biol. Chem. 1993; of from the high speed detergent-insoluble to the low speed detergent-insoluble of platelets. or human platelets were with thrombin for the and by the addition of were in and for from with are deficient in and do not transmembrane E.A. J.S. J. Biol. Chem. 1993; Scholar). In to to to the low speed detergent-insoluble pellet of platelet that were in the a for utrophin, and J.P. S. J. Biol. Chem. 1995; Scholar, E.A. J.S. J. Biol. Chem. 1993; Scholar). that Dp71Δ110 and utrophin, is of the platelet membrane cytoskeleton that is integrin-rich cytoskeletal a of transmembrane mdx3cv mice are an of DMD that are deficient in all of dystrophin and Dp71 G.A. Phelps S.F. Chamberlain J.S. Nat. Genet. 1993; 4: Scholar). To the loss of Dp71Δ110 platelet platelet adhesion to was compared in platelets from wild-type or mdx3cv mice. in in was between platelets from wild-type or mdx3cv mice platelet and were Although platelets from wild-type or mdx3cv mice to in the of platelet was between wild-type or mdx3cv platelets In thrombin-stimulated platelets from wild-type mice significantly adhesion to thrombin-stimulated platelets from mdx3cv mice that platelet adhesion to collagen in response to thrombin is decreased in mdx3cv mice, raising the possibility that Dp71Δ110 plays a role in thrombin-stimulated platelet adhesion. In the we have identified and characterized 55- to 60-kDa isoforms of Dp71 (designated Dp71Δ110) in human platelets. isoforms are to recently in human brain R.C. Morris G.E. Howard P.L. Ray P.N. Neuromusc. Disord. Scholar), are by antibodies for the C-terminal sequence of muscle dystrophin, alternative 31-amino acid C-terminal sequence due to the splicing of exon and acid terminus of The of Dp71Δ110 in the cell that these platelet proteins are by Although platelets do not to contain dystrophin or Dp71, contain utrophin, the autosomal homologue of dystrophin. The observation that adhesion to collagen in response to thrombin was significantly decreased in platelets from compared with platelets from wild-type mice, a role for Dp71Δ110 in thrombin-stimulated platelet adhesion. lines of evidence that Dp71Δ110 is a component of the platelet membrane cytoskeleton. Dp71Δ110 was in the high speed from platelets. the membrane cytoskeletal proteins vinculin and spectrin, Dp71Δ110 redistributed from the high speed detergent-insoluble to the low speed detergent-insoluble platelet by microscopy localized Dp71Δ110 in to the plasma membrane of platelets. The observation that Dp71 associates with membrane (21Cox G.A. Sunada Y. Campbell K.P. Chamberlain J.S. Nat. Genet. 1994; 8: 333-339Google Scholar, 22Greenberg D.S. Sunada Y. Campbell K.P. Yaffe D. Nudel U. Nat. Genet. 1994; 8: 340-344Google Scholar) and localizes to the plasma membrane (23Jung D. Filliol D. Metz-Boutigue M.-H. Rendon A. Neuromusc. Disord. 1993; 3: 515-518Google Scholar) provides evidence that Dp71 is a component of a submembranous cytoskeleton. provide direct evidence that Dp71Δ110 is of the membrane cytoskeleton of platelets and that it with utrophin, spectrin, and components of the membrane cytoskeleton platelet by dystrophin or utrophin, Dp71Δ110 not be expected to a membrane However, the identification of Dp71Δ110 a component of the platelet membrane cytoskeleton the possibility that it plays a role in and/or the distribution of membrane on the platelet This concept is supported by studies showing that expression of Dp71 in the muscle of mice levels of dystrophin-associated (21Cox G.A. Sunada Y. Campbell K.P. Chamberlain J.S. Nat. Genet. 1994; 8: 333-339Google Scholar, 22Greenberg D.S. Sunada Y. Campbell K.P. Yaffe D. Nudel U. Nat. Genet. 1994; 8: 340-344Google Scholar), a known component of the platelet membrane cytoskeleton, can with dystrophin, through the C-terminal domains M. C. R. A. S. G. Biochem. Res. 1993; Scholar, R. FEBS Lett. 1990; Scholar), and the the on associates with dystrophin in M. J. Biol. 1992; Scholar). Dp71Δ110 a role in by and proteins at submembranous or by 1993; Scholar, E.A. J.S. J. Biol. Chem. 1993; Scholar). studies have that a known to adhesion of can to through on the cytoskeleton A. S. K. N. J. Biol. Chem. 2002; Scholar). that is expressed in is in response to and with the cytoskeleton platelet Dp71Δ110 with or platelet platelet with cytoskeletal Like human brain contains that are alternatively spliced for exons 71–74 and 78 (14). studies have that alternative splicing of exons 71–74 in dystrophin or Dp71 the of and C.A. E. M. E. Kunkel L.M. J. Biol. Chem. 1996; Scholar, A. M. E. J. Biol. 1995; Scholar, Kunkel L.M. Nat. Genet. 1993; 3: Scholar). it is that the identified in platelets do not with Dp71Δ110 with However, Dp71Δ110 with utrophin, of the DAPC, or platelet studies are to better components of the platelet membrane cytoskeleton that with The observation that Dp71Δ110 containing the C-terminal sequence of muscle dystrophin is found in the high speed detergent-insoluble of Dp71Δ110 containing the alternative 31-amino acid C terminus are found in the high speed detergent-insoluble and high speed of that alternative splicing of exon 78 differential protein platelet In of this we have that Dp71 isoforms the alternative 31-amino acid C terminus to splicing of exon with in and P.L. R.C. Worton R.G. Ray P.N. Scholar). this with in platelets and to cytoskeletal reorganization to be splicing differential protein by the of studies have that the C-terminal of dystrophin, Dp71, can be by protein (21Cox G.A. Sunada Y. Campbell K.P. Chamberlain J.S. Nat. Genet. 1994; 8: 333-339Google Scholar, M. C. R. S. S. S. G. Biochem. J. 1993; Scholar, M. J. Biol. Chem. 1993; Scholar, R. 1994; Scholar). M. J. Biol. Chem. 1993; Scholar) that for protein within the C-terminal of dystrophin, with in exon In addition, several of the of are found in with and with the membrane cytoskeleton E.A. J.S. J. Biol. Chem. 1993; Scholar). has been that by which in in the it is not known which protein Dp71Δ110 in platelet adhesion and have been in DMD J. R. H. N. Neuromusc. Disord. 8: Scholar, N. J. H. R. Scholar), which the loss for of these F.S. F. P. J.S. G. J. B. 8: Scholar, R. J. 1992; Scholar, D. M.A. J. 1994; Scholar). The in collagen adhesion in response to thrombin in platelets from mdx3cv mice the concept that DMD is with a platelet function and the possibility that Dp71Δ110 thrombin-stimulated platelet adhesion. is that thrombin platelet cytoskeletal leading to platelet adhesion and J. and J. B. Scholar, E.A. U. G.A. Biochem. J. Scholar, 1993; Scholar, E.A. J.S. J. Biol. Chem. 1993; Scholar). that Dp71Δ110 is a component of the platelet membrane cytoskeleton and is integrin-rich cytoskeletal platelet it is that a loss of Dp71Δ110 with membrane components for platelet cytoskeletal reorganization and/or adhesion in response to In of this a in the expression of the collagen U. G.A. J. Biol. Chem. 1989; G. Scholar), has been in platelets from DMD J. R. H. N. Neuromusc. Disord. 8: Scholar). studies be to or platelet membrane components with Dp71Δ110 and loss of Dp71Δ110 to a in the of these membrane was for muscle dystrophin J.M. K. Campbell K.P. Nature. 1990; Scholar). the loss there is in that platelet adhesion to collagen in response to thrombin is reduced in mdx3cv mice the in DMD However, mdx3cv platelets are to it is that the of Dp71Δ110 not significantly Analysis of platelets from DMD with including C-terminal mutations to dystrophin and Dp71 provide a better of the function of Dp71Δ110 and role in platelet function and are to and Howard for the of this and of the Kunkel and F. M. for the Man and Morris for the monoclonal antibodies and and for the monoclonal antibody for and M. J. and E. Becker for of the of this

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