Alpha-dystroglycan, the usual suspect?
An increasing number of congenital muscular dystrophies might originate from genetic abnormalities of glycosyltransferases genes which are believed to target the alpha subunit of the dystroglycan (DG) adhesion complex as their major enzymatic substrate. alpha-DG is highly glycosylated and peripherally associated with the sarcolemma of skeletal muscle and the plasma membrane in a wide variety of cells. Several lines of evidence indicate that alpha-DG hypoglycosylation might represent the primary molecular event characterizing congenital dystrophies, since it is likely to alter alpha-DG high-affinity binding to laminin and other extracellular molecules, thus negatively influencing the basement-membrane/cytoskeleton axis and eventually leading to sarcolemmal instability, infiltration of myofibers and congenital weakness. For this reason, congenital diseases such as Walker-Warburg Syndrome or Muscle-Eye-Brain disease, have been recently denominated 'secondary dystroglycanopathies'. However, some crucial points need to be fully addressed in order to finally assess the degree of involvement of alpha-DG in congenital muscular diseases, for example: the possibility that mutations hitting the DG gene might lead to primary dystroglycanopathies; the putative functional or pathological role of hypoglycosylated - or even hyperglycosylated - alpha-DG molecules; or also the compensatory role played by the recently identified paralogue glycosyltransferases in alpha-DG sugar decoration.
Brancaccio
Andrea
A
Istituto di Chimica del Riconoscimento Molecolare, CNR c/o, Istituto di Biochimica e Biochimica Clinica, Università Cattolica del Sacro Cuore, Largo Francesco Vito n.1, 00168 Roma, Italy. andrea.brancaccio@icrm.cnr.it
D015415:Biomarkers / Q000378:metabolism; D049030:Dystroglycans / Q000378:metabolism*; D006801:Humans; D009136:Muscular Dystrophies / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism*; D009154:Mutation
D015415:Biomarkers; D049030:Dystroglycans