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Mechanisms of Disease: congenital muscular dystrophies—glycosylation takes center stage

Nature Clinical Practice Neurology volume 2, pages 222–230 (2006)Cite this article

Abstract

Recent studies have defined a group of muscular dystrophies, now termed the dystroglycanopathies, as novel disorders of glycosylation. These conditions include Walker–Warburg syndrome, muscle–eye–brain disease, Fukuyama-type congenital muscular dystrophy, congenital muscular dystrophy types 1C and 1D, and limb-girdle muscular dystrophy type 2I. Although clinical findings can be highly variable, dystroglycanopathies are all characterized by cortical malformations and ocular defects at the more severe end of the clinical spectrum, in addition to muscular dystrophy. All of these disorders are defined by the underglycosylation of α-dystroglycan. Defective glycosylation of dystroglycan severs the link between this important cell adhesion molecule and the extracellular matrix, thereby contributing to cellular pathology. Recent experiments indicate that glycosylation might not only define forms of muscular dystrophy but also provide an avenue to the development of therapies for these disorders.

Key Points

  • Mutations in 12 different genes have been shown to cause forms of congenital muscular dystrophy

  • Six of the genes associated with congenital muscular dystrophy code for molecules that are involved in the glycosylation of α-dystroglycan, a membrane protein that binds to the extracellular matrix

  • Dystroglycanopathies—diseases resulting from mutations that affect α-dystroglycan glycosylation—include Walker–Warburg syndrome, muscle–eye–brain disease, Fukuyama-type congenital muscular dystrophy, congenital muscular dystrophy types 1C and 1D, and limb-girdle muscular dystrophy type 2I

  • α-Dystroglycan is roughly half carbohydrate by molecular weight, which is largely attributable to the presence of a serine–threonine-rich domain that contains up to 55 sites for O-linked glycosylation

  • All dystroglycanopathies have the common molecular finding that α-dystroglycan is underglycosylated, and most dystroglycanopathy-associated gene products are thought to be involved in the synthesis of O-linked mannose chains on α-dystroglycan

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Figure 1: Dystroglycan glycosylation and its place in the dystrophin–glycoprotein complex.
Figure 2: Glycosylation of α-dystroglycan.

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References

  1. Jimenez-Mallebrera C et al. (2005) Congenital muscular dystrophy: molecular and cellular aspects. Cell Mol Life Sci 62: 809–823

    Article  CAS  Google Scholar 

  2. van Reeuwijk J et al. (2005) Glyc-O-genetics of Walker–Warburg syndrome. Clin Genet 67: 281–289

    Article  CAS  Google Scholar 

  3. Martin PT and Freeze HH (2003) Glycobiology of neuromuscular disorders. Glycobiology 13: 67R–75R

    Article  CAS  Google Scholar 

  4. Muntoni F et al. (2002) Defective glycosylation in muscular dystrophy. Lancet 360: 1419–1421

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  6. Endo T (2004) Structure, function and pathology of O-mannosyl glycans. Glycoconjugate J 21: 3–7

    Article  CAS  Google Scholar 

  7. Schachter H et al. (2004) The role of defective glycosylation in congenital muscular dystrophy. Glycoconjugate J 20: 291–300

    Article  CAS  Google Scholar 

  8. Endo T and Toda T (2003) Glycosylation and congenital muscular dystrophies. Biol Pharm Bull 26: 1641–1647

    Article  CAS  Google Scholar 

  9. Michele DE et al. (2002) Post-translational disruption of dystroglycan–ligand interactions in congenital muscular dystrophies. Nature 418: 417–422

    Article  CAS  Google Scholar 

  10. Beltran-Valero de Bernabe D et al. (2002) Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker–Warburg syndrome. Am J Hum Genet 71: 1033–1043

    Article  Google Scholar 

  11. van Reeuwijk J et al. (2005) POMT2 mutations cause alpha-dystroglycan hypoglycosylation and Walker–Warburg syndrome. J Med Genet 42: 907–912

    Article  CAS  Google Scholar 

  12. Yoshida A et al. (2001) Muscular dystrophy and neuronal migration disorder caused by mutations in a glycosyltransferase, POMGnT1. Dev Cell 1: 717–724

    Article  CAS  Google Scholar 

  13. Kobayashi K et al. (1998) An ancient retrotransposonal insertion causes Fukuyama-type congenital muscular dystrophy. Nature 394: 388–392

    Article  CAS  Google Scholar 

  14. Brockington M et al. (2001) Mutations in the fukutin-related protein gene (FKRP) cause a form of congenital muscular dystrophy with secondary laminin α2 deficiency and abnormal glycosylation of α-dystroglycan. Am J Hum Genet 69: 1198–1209

    Article  CAS  Google Scholar 

  15. Longman C et al. (2003) Mutations in the human LARGE gene cause MDC1D, a novel form of congenital muscular dystrophy with severe mental retardation and abnormal glycosylation of α-dystroglycan. Hum Mol Genet 12: 2853–2861

    Article  CAS  Google Scholar 

  16. Brockington M et al. (2001) 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 10: 2851–2859

    Article  CAS  Google Scholar 

  17. Qu Q and Smith FI (2004) Alpha-dystroglycan interactions affect cerebellar granule neuron migration. J Neurosci Res 76: 771–782

    Article  CAS  Google Scholar 

  18. Qu Q and Smith FI (2005) Neuronal migration defects in cerebellum of the Largemyd mouse are associated with disruptions in Bergman glia organization and delayed migration of granule neurons. Cerebellum 4: 261–270

    Article  Google Scholar 

  19. Montanaro F and Carbonetto S (2003) Targeting dystroglycan in the brain. Neuron 37: 193–196

    Article  CAS  Google Scholar 

  20. Topaloglu H et al. (2003) FKRP gene mutations cause congenital muscular dystrophy, mental retardation, and cerebellar cysts. Neurology 60: 988–992

    Article  CAS  Google Scholar 

  21. Louhichi N et al. (2004) New FKRP mutations causing congenital muscular dystrophy associated with mental retardation and central nervous system abnormalities: identification of a founder mutation in Tunisian families. Neurogenetics 5: 27–34

    Article  CAS  Google Scholar 

  22. Beltran-Valero de Bernabe D et al. (2004) Mutations in the FKRP gene can cause muscle–eye–brain disease and Walker–Warburg syndrome. J Med Gen 41: e61

    Article  CAS  Google Scholar 

  23. De Paula F et al. (2003) Asymptomatic carriers for homozygous novel mutations in the FKRP gene: the other end of the spectrum. Eur J Hum Genet 11: 923–930

    Article  CAS  Google Scholar 

  24. Kondo-Iida E et al. (1999) Novel mutations and genotype–phenotype relationships in 107 families with Fukuyama-type congenital muscular dystrophy (FCMD). Hum Mol Genet 8: 2303–2309

    Article  CAS  Google Scholar 

  25. Beltran–Valero de Bernabe D et al. (2003) A homozygous nonsense mutation in the Fukutin gene causes a Walker–Warburg syndrome phenotype. J Med Genet 40: 835–838

    Article  Google Scholar 

  26. Balci B et al. (2005) An autosomal recessive limb girdle muscular dystrophy (LGMD2) with mild mental retardation is allelic to Walker–Warburg syndrome (WWS) caused by a mutation in the POMT1 gene. Neuromuscul Disord 15: 271–275

    Article  Google Scholar 

  27. Taniguchi K et al. (2003) Worldwide distribution and broader clinical spectrum of muscle–eye–brain disease. Hum Mol Genet 12: 527–534

    Article  CAS  Google Scholar 

  28. Haliloglu G et al. (2004) Clinical spectrum of muscle–eye–brain disease: from the typical presentation to severe autistic features. Acta Myol 23: 137–139

    CAS  PubMed  Google Scholar 

  29. Ervasti JM and Campbell KP (1991) Membrane organization of the dystrophin–glycoprotein complex. Cell 66: 1121–1131

    Article  CAS  Google Scholar 

  30. Ibraghimov-Beskrovnaya O et al. (1992) Primary structure of dystrophin-associated glycoproteins linking dystrophin to the extracellular matrix. Nature 355: 696–702

    Article  CAS  Google Scholar 

  31. Martin PT (2003) Dystroglycan glycosylation and its role in matrix binding in skeletal muscle. Glycobiology 13: 55R–66R

    Article  CAS  Google Scholar 

  32. Blake DJ et al. (2002) Function and genetics of dystrophin and dystrophin-associated proteins in muscle. Physiol Rev 82: 291–329

    Article  CAS  Google Scholar 

  33. Mathews KD and Moore SA (2003) Limb-girdle muscular dystrophy. Curr Neurol Neurosci Rep 3: 78–85

    Article  Google Scholar 

  34. Chiba A et al. (1997) Structures of sialylated O-linked oligosaccharides of bovine peripheral nerve α-dystroglycan. J Biol Chem 272: 2156–2162

    Article  CAS  Google Scholar 

  35. Sasaki T et al. (1998) Detection of O-mannosyl glycans in rabbit skeletal muscle α-dystroglycan. Biochem Biophys Acta 1425: 599–606

    Article  CAS  Google Scholar 

  36. Smalheiser NR et al. (1998) Structural analysis of sequences O-linked to mannose reveals a novel Lewis X structure in cranin (dystroglycan) purified from sheep brain. J Biol Chem 273: 23689–23703

    Article  Google Scholar 

  37. Willer T et al. (2003) O-mannosyl glycans: from yeast to novel associations with human disease. Curr Opin Stru Biol 13: 621–630

    Article  CAS  Google Scholar 

  38. Moore SA et al. (2002) Deletion of brain dystroglycan recapitulates aspects of congenital muscular dystrophy. Nature 418: 422–425

    Article  CAS  Google Scholar 

  39. Saito F et al. (2003) Unique role of dystroglycan in peripheral nerve myelination, nodal structure, and sodium channel stabilization. Neuron 38: 747–758

    Article  CAS  Google Scholar 

  40. Cohn RD et al. (2002) Disruption of dag1 in differentiated skeletal muscle reveals a role for dystroglycan in muscle regeneration. Cell 110: 639–648

    Article  CAS  Google Scholar 

  41. Martin PT et al. (1999) Distinct structures and functions of related pre- and postsynaptic carbohydrates at the mammalian neuromuscular junction. Mol Cell Neurosci 13: 105–118

    Article  CAS  Google Scholar 

  42. Akasaka-Manya K et al. (2003) Mutations in the POMT1 gene found in patients with Walker–Warburg syndrome lead to a defect in protein O-mannosylation. Biochem Biophys Res Commun 325: 75–79

    Article  Google Scholar 

  43. Ichimiya T et al. (2004) The twisted abdomen phenotype of Drosophila POMT1 and POMT2 mutants coincides with their heterophilic protein O-mannosyltransferase activity. J Biol Chem 279: 42638–42647

    Article  CAS  Google Scholar 

  44. Manya H et al. (2004) Demonstration of mammalian protein O-mannosyltransferase activity: coexpression of POMT1 and POMT2 required for enzymatic activity. Proc Natl Acad Sci USA 101: 500–505

    Article  CAS  Google Scholar 

  45. Willer T et al. (2004) Targeted disruption of the Walker–Warburg syndrome gene Pomt1 in mouse results in embryonic lethality. Proc Natl Acad Sci USA 101: 14126–14131

    Article  CAS  Google Scholar 

  46. Williamson RA et al. (1997) Dystroglycan is essential for early embryonic development: disruption of Reichert's membrane in Dag-1 null mice. Hum Mol Genet 6: 831–841

    Article  CAS  Google Scholar 

  47. Jayasinha V et al. (2003) Inhibition of dystroglycan cleavage causes muscular dystrophy in transgenic mice. Neuromuscul Disord 13: 365–375

    Article  Google Scholar 

  48. Manya H et al. (2003) Loss-of-function of an N-acetylglucosaminyltransferase, POMGnT1, in muscle–eye–brain disease. Biochem Biophys Res Commun 306: 93–97

    Article  CAS  Google Scholar 

  49. Zhang W et al. (2003) Enzymatic diagnostic test for muscle–eye–brain type congenital muscular dystrophy using commercially available reagents. Clin Biochem 36: 339–344

    Article  CAS  Google Scholar 

  50. Vajsar J et al. (2006) Carriers and patients with muscle–eye–brain disease can be rapidly diagnosed by enzymatic analysis of fibroblasts and lymphoblasts. Neuromuscul Disord [doi:10.1016/j.nmd.2005.11.012]

  51. Hayashi YK et al. (2001) Selective deficiency of α-dystroglycan in Fukuyama-type congenital muscular dystrophy. Neurology 57: 115–121

    Article  CAS  Google Scholar 

  52. Matsumoto H et al. (2004) Subcellular localization of fukutin and fukutin-related protein in muscle cells. J Biochem 135: 709–712

    Article  CAS  Google Scholar 

  53. Takeda S et al. (2003) Fukutin is required for maintenance of muscle integrity, cortical histiogenesis and normal eye development. Hum Mol Genet 12: 1449–1459

    Article  CAS  Google Scholar 

  54. Torelli S et al. (2005) Sub-cellular localisation of fukutin related protein in different cell lines and in the muscle of patients with MDC1C and LGMD2I. Neuromuscul Disord 15: 836–843

    Article  Google Scholar 

  55. Brown SC et al. (2004) Abnormalities in α-dystroglycan expression in MDC1C and LGMD2I muscular dystrophies. Am J Pathol 164: 727–737

    Article  CAS  Google Scholar 

  56. Grewal PK et al. (2001) Mutant glycosyltransferase and altered glycosylation of α-dystroglycan in the myodystrophy mouse. Nature Genet 28: 151–154

    Article  CAS  Google Scholar 

  57. Barresi R et al. (2004) LARGE can functionally bypass α-dystroglycan glycoyslation defects in distinct congenital muscular dystrophies. Nature Med 10: 696–703

    Article  CAS  Google Scholar 

  58. Esko JD and Selleck SB (2002) Order out of chaos: assembly of ligand binding sites in heparan sulfate. Annu Rev Biochem 71: 435–471

    Article  CAS  Google Scholar 

  59. Patnaik SK and Stanley P (2005) Mouse large can modify complex N- and mucin O-glycans on α-dystroglycan to induce laminin binding. J Biol Chem 280: 20851–20859

    Article  CAS  Google Scholar 

  60. Combs AC and Ervasti JM (2005) Enhanced laminin binding by α-dystroglycan after enzymatic digestion. Biochem J 390: 303–309

    Article  CAS  Google Scholar 

  61. Fujimura K et al. (2005) LARGE2 facilitates the maturation of α-dystroglycan more effectively than LARGE. Biochem Biophys Res Commun 329: 1162–1171

    Article  CAS  Google Scholar 

  62. Grewal PK et al. (2005) Characterization of the LARGE family of putative glycosyltransferases associated with dystroglycanopathies. Glycobiology 15: 912–923

    Article  CAS  Google Scholar 

  63. Brockington M et al. (2005) Localization and functional analysis of the LARGE family of glycosyltransferases: significance for muscular dystrophy. Hum Mol Genet 14: 657–665

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. principal investigator in the Center for Gene Therapy at Columbus Children's Research Institute,

    Paul T Martin

  2. associate professor in the Departments of Pediatrics and Neurology at Ohio State University College of Medicine and Public Health, Columbus, OH, USA

    Paul T Martin

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Martin, P. Mechanisms of Disease: congenital muscular dystrophies—glycosylation takes center stage. Nat Rev Neurol 2, 222–230 (2006). https://doi.org/10.1038/ncpneuro0155

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