Skip to main content
SpringerLink
Log in

Muscular dystrophies due to glycosylation defects

  • Review Article
  • Published:
Neurotherapeutics

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Muntoni F, Brockington M, Blake DJ, Torelli S, Brown SC. Defective glycosylation in muscular dystrophy. Lancet 2002;360: 1419–1421.

    Article  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.

    Article  CAS  PubMed  Google Scholar 

  3. Martin PT. Congenital muscular dystrophies involving the O-man-nose pathway. Curr Mol Med 2007;7: 417–425.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Barresi RC, Campbell KP. Dystroglycan: from biosynthesis to pathogenesis of human disease. J Cell Sci 2006;119: 199–207.

    Article  CAS  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.

    Article  CAS  PubMed Central  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.

    Article  CAS  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.

    Article  CAS  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.

    Article  CAS  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.

    Article  PubMed Central  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.

    Article  PubMed Central  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.

    Article  CAS  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.

    Article  CAS  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.

    Article  CAS  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.

    Article  PubMed  Google Scholar 

  15. Michele DE, Campbell KP. Dystrophin-glycoprotein complex: post-translational processing and dystroglycan function. J Biol Chem 2003;278: 15457–15460.

    Article  CAS  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.

    Article  CAS  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.

    Article  CAS  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.

    Article  CAS  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.

    Article  CAS  PubMed  Google Scholar 

  20. Endo T. O-mannosyl glycans in mammals. Biochim Biophys Acta 1999;1473: 237–246.

    Article  CAS  PubMed  Google Scholar 

  21. Martin PT. Dystroglycan glycosylation and its role in matrix binding in skeletal muscle. Glycobiology 2003;13: 55R-66R.

    Article  CAS  PubMed  Google Scholar 

  22. Endo T, Manya H. O-mannosylation in mammalian cells. Methods Mol Biol 2006;347: 43–56.

    CAS  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.

    Article  CAS  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.

    Article  CAS  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.

    CAS  PubMed  Google Scholar 

  26. Colognato H, Winkelmann DA, Yurchenco PD. Laminin polymerization induces a receptor-cytoskeleton network. J Cell Biol 1999;145: 619–631.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Colognato H, Yurchenco PD. Form and function: the laminin family of heterotrimers. Dev Dyn 2000;218: 213–234.

    Article  CAS  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.

    Article  CAS  PubMed  Google Scholar 

  29. Combs AC, Ervasti JM. Enhanced laminin binding by alpha-dystroglycan after enzymatic deglycosylation. Biochem J 2005;390: 303–309.

    Article  CAS  PubMed Central  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(Pt 2): 209–216.

    CAS  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.

    Article  CAS  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.

    Article  CAS  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.

    Article  CAS  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.

    Article  CAS  PubMed Central  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.

    Article  CAS  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.

    Article  CAS  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.

    Article  CAS  PubMed Central  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.

    Article  CAS  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.

    Article  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.

    Article  CAS  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.

    Article  CAS  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.

    Article  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.

    Article  CAS  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.

    Article  CAS  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.

    Article  CAS  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.

    Article  CAS  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.

    Article  CAS  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.

    Article  CAS  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.

    Article  CAS  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.

    Article  CAS  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.

    Article  CAS  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.

    Article  CAS  PubMed  Google Scholar 

  53. Hirst RC, McCullagh KJ, Davies KE. Utrophin upregulation in Duchenne muscular dystrophy. Acta Myol 2005;24: 209–216.

    CAS  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.

    Article  CAS  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.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neuroscience, Dubowitz Neuromuscular Centre, UCL Institute of Child Health & Great Ormond Street Hospital, London, UK

    Francesco Muntoni, Silvia Torelli & Martin Brockington

Authors
  1. Francesco Muntoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Silvia Torelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Martin Brockington
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Francesco Muntoni.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Muntoni, F., Torelli, S. & Brockington, M. Muscular dystrophies due to glycosylation defects. Neurotherapeutics 5, 627–632 (2008). https://doi.org/10.1016/j.nurt.2008.08.005

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1016/j.nurt.2008.08.005

Key Words

Search

Navigation