Glycosylation defects in inherited muscle disease

Abstract

The gene mutated in the myodystrophy mouse, a model of muscular dystrophy, encodes a putative glycosyltransferase, Large. Mutations in genes encoding proteins thought to be involved in glycosylation have now been identified in six human forms of muscular dystrophy. Hereditary inclusion body myopathy and Nonaka myopathy result from defects in sialic acid production. Two forms of congenital muscular dystrophy, Fukuyama-type and MDC1C, result from mutations in members of the fukutin family. MDC1C and limb girdle muscular dystrophy type 2I are allelic, as they are both associated with mutations in the FKRP gene. Mutations in POMGnT, which encodes an enzyme involved in the synthesis of O-mannosyl glycans, result in muscle-eye-brain disease--another congenital form of muscular dystrophy. Abnormal alpha-dystroglycan has been reported in the myodystrophy mouse, and in the congenital and limb girdle muscular dystrophies. Recent data have shown that there is altered glycosylation of the protein and that this reduces its ability to bind to extracellular matrix ligands such as laminin and agrin.

Congenital muscular dystrophy. Part II: a review of pathogenesis and therapeutic perspectives

“…Molecular changes in genes that codified glycosyltransferases affecting this step of the DAG chain of links are responsible for the pathogenesis of five CMDs named alpha-dystroglycanopathies or CMDs by defects of the omannosyl-glycosylation of alpha-DG [1][2][3][4][5][6][7]15,30,33,[36][37][38][39][40][41][42][43][44][45][46][47][48][49][50] : Fukuyama CMD (FCMD), "muscle-eye-brain" (MeB) disease, WalkerWarburg syndrome (WWs), MDC1C and MCD1D.…”

“…The recognition of the involvement of other two glycosyltransferases, PoMT1 and PoMT2, in the pathogenesis of CMDs came soon after [155][156] . During the last seven years, many have discussed and elucidated the pathogenesis of the defective glycosylation of alpha-DG, and the particular cortical involvement that is observed in many of them 5,711,13,15,17,18,30,33,34,[36][37][38][39][40][41][42][43][44][45][46][47][157][158][159][160][161] . It is supposed that other subtypes of CMD will prove to depend on mutations in genes as yet unidentified but also involved in alpha-DG glycosylation 39,45,46,48 .…”

“…It is supposed that other subtypes of CMD will prove to depend on mutations in genes as yet unidentified but also involved in alpha-DG glycosylation 39,45,46,48 . In addition, from the first reports on congenital disorders of glycosylation, it seemed unlikely that the glycosyltransferases could have a role only in glycosylation of alpha-DG and the importance of looking for other protein targets has been emphasized 37,38 .…”

“…The researches about the long-term potential of glycotherapies for CMD have begun with the first reports about the defective alpha-DG glycosylation as a new pathogenic mechanism for some subtypes of 7,11,13,15,[32][33][34][36][37][38][39][40][41][42][43][44][45][46][47][48]157,176,177 . The central point of these researches is that the overexpression of lArGe promotes the attachement of glycans to alpha-DG, therefore restoring its ligandbinding function 178 .…”

“…In addition to the potentially therapeutic overexpression of lArGe 1 and 2, other possible strategies have been discussed 37,38,40,178,180,181 : to obtain synthetic donors of sugars that could serve as glycan analogues; to carry on enzyme replacement via gene therapy, and to provide ectopic expression or upregulation of other glycosyltransferases that might compensate the loss of function of that altered by the mutation. A similar mechanism has been tested in a mouse model of Duchenne muscular dystrophy in which the dystrophic process was inhibited by the overexpression of Galgt2, another glycosyltransferase not implicated in CMD 48,176,182 .…”