Recently, post-translational modification of
proteins has been defined as a new area of focus for
muscular dystrophy research by the identification of a group of disease genes that encode known or putative glycosylation
enzymes.
Walker-Warburg Syndrome (WWS) and
muscle-eye-brain disease (MEB) are caused by mutations in two genes involved in O-mannosylation, POMT1 and
POMGnT1, respectively.
Fukuyama muscular dystrophy (FCMD) is due to mutations in fukutin, a putative phospholigand
transferase. Congenital
muscular dystrophy type 1C and
limb girdle muscular dystrophy type 2I are allelic, both being due to mutations in the gene-encoding fukutin-related
protein (FKRP). Finally, the causative gene in the
myodystrophy (myd) mouse is a putative bifunctional
glycosyltransferase (Large). WWS, MEB, FCMD and the myd mouse are also associated with neuronal migration abnormalities (often type II
lissencephaly) and ocular or
retinal defects. A deficiency in post-translational modification of
alpha-dystroglycan is a common feature of all these
muscular dystrophies and is thought to involve O-glycosylation pathways. This abnormally modified
alpha-dystroglycan is deficient in binding to extracellular matrix
ligands, including
laminin and
agrin. Selective deletion of
dystroglycan in the central nervous system (CNS) produces brain abnormalities with striking similarities to WWS, MEB, FCMD and the myd mouse. Thus, impaired
dystroglycan function is strongly implicated in these diseases. However, it is unlikely that these five glycosylation
enzymes only have a role in glycosylation of
alpha-dystroglycan and it is important that other
protein targets are identified.