Elsevier

The Lancet

Volume 360, Issue 9343, 2 November 2002, Pages 1419-1421
The Lancet

Rapid Review
Defective glycosylation in muscular dystrophy

https://doi.org/10.1016/S0140-6736(02)11397-3Get rights and content

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Glycosylation defects and disease

Defects in glycosylation pathways in human disease were initially identified in 1980 by Jaeken et al following the observation of abnormal processing of thyroxin-binding globulin and arylsulphatase-A in patients with psychomotor retardation.6 Thirteen congenital disorders of glycosylation (CDGs) have been identified to date and they almost invariably affect N-glycan assembly (CDG type I) or processing (CDG type II).7 Common features of patients with CDG include varying combinations of

The role of α-dystroglycan

α-dystroglycan is a peripheral membrane component of the dystrophin-glycoprotein complex (DGC) common to several tissues including muscle, nerve, heart, and brain.9, 10 In muscle, this complex functions by linking the actinassociated cytoskeleton of the muscle fibre to the extracellular matrix via dystrophin and the laminin α2 chain of merosin (figure). The DGC is disrupted in several different forms of muscular dystrophy.11 Mutations in dystrophin cause Duchenne and Becker muscular

Glycosyltransferases and CMD (panel)

Muscular dystrophies secondary to mutations in genes encoding for glycosyltransferases

ConditionGeneProtein functionClinical featuresMuscle α-dystroglycan
Muscle-eye-brain disease (MEB)POMGnT1O-mannosyl glycan synthesisSevere muscle weaknessAbsent on IHC and western blot*
Mental retardation
Epilepsy
Neuronal migration disorder
Ocular abnormalities
Fukuyama congenital muscular dystrophyFukutinPutative glycosyl-transferaseSevere proximal and axial weakness Mental retardationAbsent on IHC and western blot

Recent advances

The association of abnormal glycosylation of α-dystroglycan with muscular dystrophy has now been confirmed and extended by work originating from Kevin Campbell's laboratory.25, 26 Using a new antibody raised against a non-glycosylated portion of the molecule, α-dystroglycan was shown to be present in MEB, FCMD, and the myd mouse, but in a hypoglycosylated form that leads to loss of immunoreactivity with the antibodies used in the earlier studies.25 Furthermore, these investigators showed a

Future directions

Several forms of muscular dystrophy have now been shown to be due to defects in glycosyltransferases, abnormalities in which give rise to multisystem disorders. The precise substrates of these enzymes have yet to be fully determined. The glycosylation of α-dystroglycan in both muscle and brain appears to have an essential role in these conditions and sheds further light on the pathophysiology of muscle survival and neuronal migration. However, other muscle glycoproteins might also be affected

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References (27)

  • P Van den Steen et al.

    Concepts and principles of O-linked glycosylation

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    (1998)
  • J Jaeken et al.

    Familial psychomotor retardation with markedly fluctuating serum proteins, FSH and GH levels, partial TGB-deficiency, increased serum arysulfatase A and increased CSF proteins: a new syndrome?

    Pediatr Res

    (1980)
  • J Jaeken et al.

    Congenital disorders of glycosylation

    Annu Rev Genomics Hum Genet

    (2001)
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