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. 2008 Oct 1;5(4):627–632. doi: 10.1016/j.nurt.2008.08.005

Muscular dystrophies due to glycosylation defects

Francesco Muntoni 1,✉, Silvia Torelli 1, Martin Brockington 1
PMCID: PMC4514705  PMID: 19019316

Summary

In the last few years, muscular dystrophies due to reduced glycosylation of alpha-dystroglycan (ADG) have emerged as a common group of conditions, now referred to as dystroglycanopathies. Mutations in six genes (POMT1, POMT2, POMGnT1, Fukutin, FKRP and LARGE) have so far been identified in patients with a dystroglycanopathy. Allelic mutations in each of these genes can result in a wide spectrum of clinical conditions, ranging from severe congenital onset with associated structural brain malformations (Walker Warburg syndrome; muscle-eye-brain disease; Fukuyama muscular dystrophy; congenital muscular dystrophy type 1D) to a relatively milder congenital variant with no brain involvement (congenital muscular dystrophy type 1C), and to limb-girdle muscular dystrophy (LGMD) type 2 variants with onset in childhood or adult life (LGMD2I, LGMD2L, and LGMD2N).

ADG is a peripheral membrane protein that undergoes multiple and complex glycosylation steps to regulate its ability to effectively interact with extracellular matrix proteins, such as laminin, agrin, and perlecan.

Although the precise composition of the glycans present on ADG are not known, it has been demonstrated that the forced overexpression of LARGE, or its paralog LARGE2, is capable of increasing the glycosylation of ADG in normal cells. In addition, its overexpression is capable of restoring dystroglycan glycosylation and laminin binding properties in primary cell cultures of patients affected by different genetically defined dystroglycanopathy variants.

These observations suggest that there could be a role for therapeutic strategies to overcome the glycosylation defect in these conditions via the overexpression of LARGE.

Key Words: Alpha dystroglycan, glycosylation, O-mannosylation, laminin binding, pharmacological upregulation

References

  • 1.Muntoni F, Brockington M, Blake DJ, Torelli S, Brown SC. Defective glycosylation in muscular dystrophy. Lancet. 2002;360:1419–1421. doi: 10.1016/S0140-6736(02)11397-3. [DOI] [PubMed] [Google Scholar]
  • 2.Muntoni F, Brockington M, Torelli S, Brown SC. Defective glycosylation in congenital muscular dystrophies. Curr Opin Neurol. 2004;17:205–209. doi: 10.1097/00019052-200404000-00020. [DOI] [PubMed] [Google Scholar]
  • 3.Martin PT. Congenital muscular dystrophies involving the O-man-nose pathway. Curr Mol Med. 2007;7:417–425. doi: 10.2174/156652407780831601. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Barresi RC, Campbell KP. Dystroglycan: from biosynthesis to pathogenesis of human disease. J Cell Sci. 2006;119:199–207. doi: 10.1242/jcs.02814. [DOI] [PubMed] [Google Scholar]
  • 5.Brockington M, Blake DJ, Prandini P, et al. Mutations in the fukutin-related protein gene (FKRP) cause a form of congenital muscular dystrophy with secondary laminin alpha2 deficiency and abnormal glycosylation of alpha-dystroglycan. Am J Hum Genet. 2001;69:1198–1209. doi: 10.1086/324412. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Brockington M, Yuva Y, Prandini P, et al. Mutations in the fukutin-related protein gene (FKRP) identify limb girdle muscular dystrophy 2I as a milder allelic variant of congenital muscular dystrophy MDC1C. Hum Mol Genet. 2001;10:2851–2859. doi: 10.1093/hmg/10.25.2851. [DOI] [PubMed] [Google Scholar]
  • 7.Godfrey C, Escolar D, Brockington M, et al. Fukutin gene mutations in steroid-responsive limb girdle muscular dystrophy. Ann Neurol. 2006;60:603–610. doi: 10.1002/ana.21006. [DOI] [PubMed] [Google Scholar]
  • 8.Biancheri R, Falace A, Tessa A, et al. POMT2 gene mutation in limb-girdle muscular dystrophy with inflammatory changes. Biochem Biophys Res Commun. 2007;363:1033–1037. doi: 10.1016/j.bbrc.2007.09.066. [DOI] [PubMed] [Google Scholar]
  • 9.Beltran-Valero de Bernabe D, Currier S, Steinbrecher A, et al. Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker-Warburg syndrome. Am J Hum Genet. 2002;71:1033–1043. doi: 10.1086/342975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.van Reeuwijk J, Janssen M, van den Elzen C, et al. POMT2 mutations cause alpha-dystroglycan hypoglycosylation and Walker-Warburg syndrome. J Med Genet. 2005;42:907–912. doi: 10.1136/jmg.2005.031963. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Yoshida A, Kobayashi K, Manya H, et al. Muscular dystrophy and neuronal migration disorder caused by mutations in a glycosyl-transferase, POMGnT1. Dev Cell. 2001;1:717–724. doi: 10.1016/S1534-5807(01)00070-3. [DOI] [PubMed] [Google Scholar]
  • 12.Kobayashi K, Nakahori Y, Miyake M, et al. An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy. Nature. 1998;394:388–392. doi: 10.1038/28256. [DOI] [PubMed] [Google Scholar]
  • 13.Longman C, Brockington M, Torelli S, et al. 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. 2003;12:2853–2861. doi: 10.1093/hmg/ddg307. [DOI] [PubMed] [Google Scholar]
  • 14.Godfrey C, Clement E, Mein R, et al. Refining genotype phenotype correlations in muscular dystrophies with defective glycosylation of dystroglycan. Brain. 2007;130:2725–2735. doi: 10.1093/brain/awm212. [DOI] [PubMed] [Google Scholar]
  • 15.Michele DE, Campbell KP. Dystrophin-glycoprotein complex: post-translational processing and dystroglycan function. J Biol Chem. 2003;278:15457–15460. doi: 10.1074/jbc.R200031200. [DOI] [PubMed] [Google Scholar]
  • 16.Henry MD, Campbell KP. Dystroglycan: an extracellular matrix receptor linked to the cytoskeleton. Curr Opin Cell Biol. 1996;8:625–631. doi: 10.1016/S0955-0674(96)80103-7. [DOI] [PubMed] [Google Scholar]
  • 17.Holt KH, Crosbie RH, Venzke DP, Campbell KP. Biosynthesis of dystroglycan: processing of a precursor propeptide. FEBS Lett. 2000;468:79–83. doi: 10.1016/S0014-5793(00)01195-9. [DOI] [PubMed] [Google Scholar]
  • 18.McDearmon EL, Combs AC, Ervasti JM. Differential Vicia villosa agglutinin reactivity identifies three distinct dystroglycan complexes in skeletal muscle. J Biol Chem. 2001;276:35078–35086. doi: 10.1074/jbc.M103843200. [DOI] [PubMed] [Google Scholar]
  • 19.McDearmon EL, Combs AC, Ervasti JM. Core 1 glycans on alpha-dystroglycan mediate laminin-induced acetylcholine receptor clustering but not laminin binding. J Biol Chem. 2003;278:44868–44873. doi: 10.1074/jbc.M307026200. [DOI] [PubMed] [Google Scholar]
  • 20.Endo T. O-mannosyl glycans in mammals. Biochim Biophys Acta. 1999;1473:237–246. doi: 10.1016/S0304-4165(99)00182-8. [DOI] [PubMed] [Google Scholar]
  • 21.Martin PT. Dystroglycan glycosylation and its role in matrix binding in skeletal muscle. Glycobiology. 2003;13:55R–66R. doi: 10.1093/glycob/cwg076. [DOI] [PubMed] [Google Scholar]
  • 22.Endo T, Manya H. O-mannosylation in mammalian cells. Methods Mol Biol. 2006;347:43–56. doi: 10.1385/1-59745-167-3:43. [DOI] [PubMed] [Google Scholar]
  • 23.Hoyte K, Kang C, Martin PT. Definition of pre- and postsynaptic forms of the CT carbohydrate antigen at the neuromuscular junction: ubiquitous expression of the CT antigens and the CT GalNAc transferase in mouse tissues. Brain Res Mol Brain Res. 2002;109:146–160. doi: 10.1016/S0169-328X(02)00551-X. [DOI] [PubMed] [Google Scholar]
  • 24.Smalheiser NR, Kim E. Purification of cranin, a laminin binding membrane protein. Identity with dystroglycan and reassessment of its carbohydrate moieties. J Biol Chem. 1995;270:15425–15433. doi: 10.1074/jbc.270.25.15425. [DOI] [PubMed] [Google Scholar]
  • 25.Henry MD, Satz JS, Brakebusch C, et al. Distinct roles for dystroglycan, betal integrin and perlecan in cell surface laminin organization. J Cell Sci. 2001;114:1137–1144. doi: 10.1242/jcs.114.6.1137. [DOI] [PubMed] [Google Scholar]
  • 26.Colognato H, Winkelmann DA, Yurchenco PD. Laminin polymerization induces a receptor-cytoskeleton network. J Cell Biol. 1999;145:619–631. doi: 10.1083/jcb.145.3.619. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Colognato H, Yurchenco PD. Form and function: the laminin family of heterotrimers. Dev Dyn. 2000;218:213–234. doi: 10.1002/(SICI)1097-0177(200006)218:2<213::AID-DVDY1>3.0.CO;2-R. [DOI] [PubMed] [Google Scholar]
  • 28.Yurchenco PD, Cheng YS, Campbell K, Li S. Loss of basement membrane, receptor and cytoskeletal lattices in a laminin-deficient muscular dystrophy. J Cell Sci. 2004;117:735–742. doi: 10.1242/jcs.00911. [DOI] [PubMed] [Google Scholar]
  • 29.Combs AC, Ervasti JM. Enhanced laminin binding by alpha-dystroglycan after enzymatic deglycosylation. Biochem J. 2005;390:303–309. doi: 10.1042/BJ20050375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Brown SC, Fassati A, Popplewell L, et al. Dystrophic phenotype induced in vitro by antibody blockade of muscle alpha-dystrogly-can-laminin interaction. J Cell Sci. 1999;112:209–216. doi: 10.1242/jcs.112.2.209. [DOI] [PubMed] [Google Scholar]
  • 31.Ishii H, Hayashi YK, Nonaka I, Arahata K. Electron microscopic examination of basal lamina in Fukuyama congenital muscular dystrophy. Neuromuscul Disord. 1997;7:191–197. doi: 10.1016/S0960-8966(97)00462-8. [DOI] [PubMed] [Google Scholar]
  • 32.Sabatelli P, Columbaro M, Mura I, et al. Extracellular matrix and nuclear abnormalities in skeletal muscle of a patient with Walker-Warburg syndrome caused by POMT1 mutation. Biochim Biophys Acta. 2003;1638:57–62. doi: 10.1016/S0925-4439(03)00040-1. [DOI] [PubMed] [Google Scholar]
  • 33.Hu H, Yang Y, Eade A, Xiong Y, Qi Y. Breaches of the pial basement membrane and disappearance of the glia limitans during development underlie the cortical lamination defect in the mouse model of muscle-eye-brain disease. J Comp Neurol. 2007;501:168–183. doi: 10.1002/cne.21238. [DOI] [PubMed] [Google Scholar]
  • 34.Brown SC, Torelli S, Brockington M, et al. Abnormalities in alpha-dystroglycan expression in MDC1C and LGMD2I muscular dystrophies. Am J Pathol. 2004;164:727–737. doi: 10.1016/S0002-9440(10)63160-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Akasaka-Manya K, Manya H, Kobayashi K, Toda T, Endo T. Structure-function analysis of human protein O-linked mannose betal,2-N-acetylglucosaminyltransferase 1, POMGnTl. Biochem Biophys Res Commun. 2004;320:39–44. doi: 10.1016/j.bbrc.2004.05.129. [DOI] [PubMed] [Google Scholar]
  • 36.Manya H, Sakai K, Kobayashi K, et al. Loss-of-function of an N-acetylglucosaminyltransferase, POMGnT1, in muscle-eye-brain disease. Biochem Biophys Res Commun. 2003;306:93–97. doi: 10.1016/S0006-291X(03)00924-0. [DOI] [PubMed] [Google Scholar]
  • 37.Manya H, Chiba A, Yoshida A, et al. Demonstration of mammalian protein O-mannosyltransferase activity: coexpression of POMT1 and POMT2 required for enzymatic activity. Proc Natl Acad Sci U S A. 2004;101:500–505. doi: 10.1073/pnas.0307228101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Xiong H, Kobayashi K, Tachikawa M, et al. Molecular interaction between fukutin and POMGnT1 in the glycosylation pathway of alpha-dystroglycan. Biochem Biophys Res Commun. 2006;350:935–941. doi: 10.1016/j.bbrc.2006.09.129. [DOI] [PubMed] [Google Scholar]
  • 39.de Paula F, Vieira N, Starling A, et al. Asymptomatic carriers for homozygous novel mutations in the FKRP gene: the other end of the spectrum. Eur J Hum Genet. 2003;11:923–930. doi: 10.1038/sj.ejhg.5201066. [DOI] [PubMed] [Google Scholar]
  • 40.Brockington M, Torelli S, Prandini P, et al. Localization and functional analysis of the LARGE family of glycosyltransferases: significance for muscular dystrophy. Hum Mol Genet. 2005;14:657–665. doi: 10.1093/hmg/ddi062. [DOI] [PubMed] [Google Scholar]
  • 41.Esapa CT, Benson MA, Schroder JE, et al. Functional requirements for fukutin-related protein in the Golgi apparatus. Hum Mol Genet. 2002;11:3319–3331. doi: 10.1093/hmg/11.26.3319. [DOI] [PubMed] [Google Scholar]
  • 42.Torelli S, Brown SC, Brockington M, et al. Sub-cellular localisation of fukutin related protein in different cell lines and in the muscle of patients with MDC1C and LGMD2I. Neuromuscul Disord. 2005;15:836–843. doi: 10.1016/j.nmd.2005.09.004. [DOI] [PubMed] [Google Scholar]
  • 43.Dolatshad NF, Brockington M, Torelli S, et al. Mutated fukutin-related protein (FKRP) localises as wild type in differentiated muscle cells. Exp Cell Res. 2005;309:370–378. doi: 10.1016/j.yexcr.2005.06.017. [DOI] [PubMed] [Google Scholar]
  • 44.Matsumoto H, Noguchi S, Sugie K, et al. Subcellular localization of fukutin and fukutin-related protein in muscle cells. J Biochem (Tokyo) 2004;135:709–712. doi: 10.1093/jb/mvh086. [DOI] [PubMed] [Google Scholar]
  • 45.Beedle AM, Nienaber PM, Campbell KP. Fukutin-related protein associates with the sarcolemmal dystrophin-glycoprotein complex. J Biol Chem. 2007;282:16713–16717. doi: 10.1074/jbc.C700061200. [DOI] [PubMed] [Google Scholar]
  • 46.Esapa CT, McIlhinney RA, Blake DJ. Fukutin-related protein mutations that cause congenital muscular dystrophy result in ER-retention of the mutant protein in cultured cells. Hum Mol Genet. 2005;14:295–305. doi: 10.1093/hmg/ddi026. [DOI] [PubMed] [Google Scholar]
  • 47.Grewal PK, Holzfeind PJ, Bittner RE, Hewitt JE. Mutant glycosyltransferase and altered glycosylation of alpha-dystroglycan in the myodystrophy mouse. Nat Genet. 2001;28:151–154. doi: 10.1038/88865. [DOI] [PubMed] [Google Scholar]
  • 48.Grewal PK, McLaughlan JM, Moore CJ, Browning CA, Hewitt JE. Characterization of the LARGE family of putative glycosyltransferases associated with dystroglycanopathies. Glycobiology. 2005;15:912–923. doi: 10.1093/glycob/cwi094. [DOI] [PubMed] [Google Scholar]
  • 49.Kanagawa M, Saito F, Kunz S, et al. Molecular recognition by LARGE is essential for expression of functional dystroglycan. Cell. 2004;117:953–964. doi: 10.1016/j.cell.2004.06.003. [DOI] [PubMed] [Google Scholar]
  • 50.Barresi R, Michele DE, Kanagawa M, et al. LARGE can functionally bypass alpha-dystroglycan glycosylation defects in distinct congenital muscular dystrophies. Nat Med. 2004;10:696–703. doi: 10.1038/nm1059. [DOI] [PubMed] [Google Scholar]
  • 51.Patnaik SK, Stanley P. Mouse large can modify complex N- and mucin O-glycans on alpha-dystroglycan to induce laminin binding. J Biol Chem. 2005;280:20851–20859. doi: 10.1074/jbc.M500069200. [DOI] [PubMed] [Google Scholar]
  • 52.Gambari R, Fibach E. Medicinal chemistry of fetal hemoglobin inducers for treatment of beta-thalassemia. Curr Med Chem. 2007;14:199–212. doi: 10.2174/092986707779313318. [DOI] [PubMed] [Google Scholar]
  • 53.Hirst RC, McCullagh KJ, Davies KE. Utrophin upregulation in Duchenne muscular dystrophy. Acta Myol. 2005;24:209–216. [PubMed] [Google Scholar]
  • 54.Cohn RD, Henry MD, Michele DE, et al. Disruption of DAG1 in differentiated skeletal muscle reveals a role for dystroglycan in muscle regeneration. Cell. 2002;110:639–648. doi: 10.1016/S0092-8674(02)00907-8. [DOI] [PubMed] [Google Scholar]
  • 55.Moore SA, Saito F, Chen J, et al. Deletion of brain dystroglycan recapitulates aspects of congenital muscular dystrophy. Nature. 2002;418:422–425. doi: 10.1038/nature00838. [DOI] [PubMed] [Google Scholar]

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