Neurotherapeutics

, Volume 5, Issue 4, pp 627–632

Muscular dystrophies due to glycosylation defects

  • Francesco Muntoni
  • Silvia Torelli
  • Martin Brockington
Review Article

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 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Muntoni F, Brockington M, Blake DJ, Torelli S, Brown SC. Defective glycosylation in muscular dystrophy. Lancet 2002;360: 1419–1421.PubMedCrossRefGoogle Scholar
  2. 2.
    Muntoni F, Brockington M, Torelli S, Brown SC. Defective glycosylation in congenital muscular dystrophies. Curr Opin Neurol 2004;17: 205–209.PubMedCrossRefGoogle Scholar
  3. 3.
    Martin PT. Congenital muscular dystrophies involving the O-man-nose pathway. Curr Mol Med 2007;7: 417–425.PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Barresi RC, Campbell KP. Dystroglycan: from biosynthesis to pathogenesis of human disease. J Cell Sci 2006;119: 199–207.PubMedCrossRefGoogle Scholar
  5. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 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.PubMedCrossRefGoogle Scholar
  7. 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.PubMedCrossRefGoogle Scholar
  8. 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.PubMedCrossRefGoogle Scholar
  9. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 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.PubMedCrossRefGoogle Scholar
  12. 12.
    Kobayashi K, Nakahori Y, Miyake M, et al. An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy. Nature 1998;394: 388–392.PubMedCrossRefGoogle Scholar
  13. 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.PubMedCrossRefGoogle Scholar
  14. 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.PubMedCrossRefGoogle Scholar
  15. 15.
    Michele DE, Campbell KP. Dystrophin-glycoprotein complex: post-translational processing and dystroglycan function. J Biol Chem 2003;278: 15457–15460.PubMedCrossRefGoogle Scholar
  16. 16.
    Henry MD, Campbell KP. Dystroglycan: an extracellular matrix receptor linked to the cytoskeleton. Curr Opin Cell Biol 1996;8: 625–631.PubMedCrossRefGoogle Scholar
  17. 17.
    Holt KH, Crosbie RH, Venzke DP, Campbell KP. Biosynthesis of dystroglycan: processing of a precursor propeptide. FEBS Lett 2000;468: 79–83.PubMedCrossRefGoogle Scholar
  18. 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.PubMedCrossRefGoogle Scholar
  19. 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.PubMedCrossRefGoogle Scholar
  20. 20.
    Endo T. O-mannosyl glycans in mammals. Biochim Biophys Acta 1999;1473: 237–246.PubMedCrossRefGoogle Scholar
  21. 21.
    Martin PT. Dystroglycan glycosylation and its role in matrix binding in skeletal muscle. Glycobiology 2003;13: 55R-66R.PubMedCrossRefGoogle Scholar
  22. 22.
    Endo T, Manya H. O-mannosylation in mammalian cells. Methods Mol Biol 2006;347: 43–56.PubMedGoogle Scholar
  23. 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.PubMedCrossRefGoogle Scholar
  24. 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.PubMedCrossRefGoogle Scholar
  25. 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.PubMedGoogle Scholar
  26. 26.
    Colognato H, Winkelmann DA, Yurchenco PD. Laminin polymerization induces a receptor-cytoskeleton network. J Cell Biol 1999;145: 619–631.PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Colognato H, Yurchenco PD. Form and function: the laminin family of heterotrimers. Dev Dyn 2000;218: 213–234.PubMedCrossRefGoogle Scholar
  28. 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.PubMedCrossRefGoogle Scholar
  29. 29.
    Combs AC, Ervasti JM. Enhanced laminin binding by alpha-dystroglycan after enzymatic deglycosylation. Biochem J 2005;390: 303–309.PubMedCentralPubMedCrossRefGoogle Scholar
  30. 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(Pt 2): 209–216.PubMedGoogle Scholar
  31. 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.PubMedCrossRefGoogle Scholar
  32. 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.PubMedCrossRefGoogle Scholar
  33. 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.PubMedCrossRefGoogle Scholar
  34. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  35. 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.PubMedCrossRefGoogle Scholar
  36. 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.PubMedCrossRefGoogle Scholar
  37. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  38. 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.PubMedCrossRefGoogle Scholar
  39. 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.PubMedCrossRefGoogle Scholar
  40. 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.PubMedCrossRefGoogle Scholar
  41. 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.PubMedCrossRefGoogle Scholar
  42. 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.PubMedCrossRefGoogle Scholar
  43. 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.PubMedCrossRefGoogle Scholar
  44. 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.CrossRefGoogle Scholar
  45. 45.
    Beedle AM, Nienaber PM, Campbell KP. Fukutin-related protein associates with the sarcolemmal dystrophin-glycoprotein complex. J Biol Chem 2007;282: 16713–16717.PubMedCrossRefGoogle Scholar
  46. 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.PubMedCrossRefGoogle Scholar
  47. 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.PubMedCrossRefGoogle Scholar
  48. 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.PubMedCrossRefGoogle Scholar
  49. 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.PubMedCrossRefGoogle Scholar
  50. 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.PubMedCrossRefGoogle Scholar
  51. 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.PubMedCrossRefGoogle Scholar
  52. 52.
    Gambari R, Fibach E. Medicinal chemistry of fetal hemoglobin inducers for treatment of beta-thalassemia. Curr Med Chem 2007;14: 199–212.PubMedCrossRefGoogle Scholar
  53. 53.
    Hirst RC, McCullagh KJ, Davies KE. Utrophin upregulation in Duchenne muscular dystrophy. Acta Myol 2005;24: 209–216.PubMedGoogle Scholar
  54. 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.PubMedCrossRefGoogle Scholar
  55. 55.
    Moore SA, Saito F, Chen J, et al. Deletion of brain dystroglycan recapitulates aspects of congenital muscular dystrophy. Nature 2002;418: 422–425.PubMedCrossRefGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2008

Authors and Affiliations

  • Francesco Muntoni
    • 1
  • Silvia Torelli
    • 1
  • Martin Brockington
    • 1
  1. 1.Department of Neuroscience, Dubowitz Neuromuscular CentreUCL Institute of Child Health & Great Ormond Street HospitalLondonUK

Personalised recommendations