1 Alpha - Dystroglycanopathy Mieko

Alpha-dystroglycanopathies are a clinically and genetically heterogenous group of muscular dystrophies characterized by the reduced or absent glycosylation of alpha-dystroglycan (Muntoni et al., 2002). The hypoglycosylation of alpha-dystroglycan leads to decreased binding of its ligands, including laminin, agrin and perlecan in skeletal muscle and neurexin in the brain. The only known target for this type of glycosylation is alpha-dystroglycan, and together with other proteins of the dystrophin-glycoprotein complex it forms a link between extracellular matrix proteins and actin cytoskeleton. The clinical manifestations of alphadystroglycanopathies are extremely variable, leading to a broad spectrum of phenotypes with limb-girdle muscular dystrophy (LGMD) without mental retardation delineating the milder end, and Walker-Warburg syndrome (WWS), muscle-eye-brain disease (MEB) and Fukuyama type congenital muscular dystrophy (FCMD) the severe end (Muntoni & Voit, 2004) (Fig. 1). In most of the severe disorders, the eyes and the brain are affected in addition to congenital muscular dystrophy (CMD). Here, CMD is defined as onset of weakness prenatally or within the first 6 months of life, and LGMD is defined by later onset weakness, specifically after having acquired ambulation. The brain abnormalities are described as cobblestone lissencephaly; available pathological studies have demonstrated breeches of the glia limitans and over-migration of cortical neurons into the pial spaces. In WWS, the lifespan of patients is severely reduced and brain and eye abnormalities extremely severe (Dobyns et al., 1989); MEB and FCMD patients generally survive beyond infancy, ocular manifestations are usually milder in FCMD than in MEB (Fukuyama et al., 1981, Santavuori et al., 1989). To date, mutations in six genes which encode putative or confirmed glycosyltransferases have been identified in these autosomal recessively inherited disorders: Protein-O-mannosyl transferase 1 and 2 (POMT1 and POMT2), Protein-O-mannose 1,2-Nacetylglucosaminyltransferase 1 (POMGnT1), Fukutin-related protein (FKRP), Fukutin (FKTN), and LARGE. Initially, each gene was associated with one syndrome (original phenotype) : POMT1 and POMT2 mutations giving rise to WWS; POMGnT1 mutations in patients with MEB; FKRP mutations in patients with congenital or late-onset muscular dystrophies (MDC1C and LGMD 2I); FKTN mutations in patients with FCMD; LARGE mutations in a patient with congenital muscular dystrophy type 1D (MDC 1D). Subsequently, mutation analysis in patients with milder or more severe syndromes within the dystroglycanopathy spectrum demonstrated allelic heterogeneity for different mutations in each of the dystroglycanopathy genes (Fig. 1). Null mutations in POMT1, POMT2, POMGnT1, FKRP,