α-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 α subunit of the dystroglycan (DG) adhesion complex as their major enzymatic substrate. α-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 α-DG hypoglycosylation might represent the primary molecular event characterizing congenital dystrophies, since it is likely to alter α-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 α-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 - α-DG molecules; or also the compensatory role played by the recently identified paralogue glycosyltransferases in α-DG sugar decoration.