G.P.11 Fukutin-related protein (FKRP) is involved in the post-phosphoryl modification of α-dystroglycan

Abstract

Aberrant glycosylation of α-dystroglycan (α-DG) with reduced laminin-binding activity is a biochemical hallmark of a group of muscular dystrophy commonly referred to as dystroglycanopathy. Among causative genes for dystroglycanopathy, it has been reported that fukutin and LARGE are involved in phosphodiester-linked modification of O-mannose on α-DG. Fukutin-related protein (FKRP) is a responsible gene of dystroglycanopathy, however its precise function is still unknown. In this study, we use several dystroglycanopathy mouse models to demonstrate that FKRP is also involved in the phosphodiester-linked modification. Furthermore, we have found that the glycosylation status of α-DG in lung and testis is minimally affected by defects in fukutin, LARGE or FKRP. α-DG prepared from wild-type lung- or testis-derived cells lacks the post-phosphoryl moiety and shows little laminin-binding activity. These results suggest that post-phosphoryl modification not only plays critical roles in the pathogenesis of dystroglycanopathy but also is a key determinant of α-DG functional expression as a laminin receptor in normal tissues and cells.