Fukutin-Related Protein Alters the Deposition of Laminin in the Eye and Brain

Mutations in fukutin-related protein (FKRP) are responsible for acommongroup of muscular dystrophies ranging from adult onset limb girdle muscular dystrophies to severe congenital forms with associated structural brain involvement. The defining feature of this group of disorders is the hypoglycosylation of a-dystroglycan and its inability to effectively bind extracellular matrix ligands such as laminin a 2. However, a-dystroglycan has the potential to interact with a number of laminin isoforms many of which are basement membrane/ tissue specific and developmentally regulated. To further investigate this we evaluated laminin a-chain expression in the cerebral cortex and eye of our FKRP knock-down mouse (FKRPKD). These mice showed a marked disturbance in the deposition of laminin a-chains including a1, a2, a4, and a5, although only laminin a1-and ?1-chain mRNA expression was significantly upregulated relative to controls. Moreover, there was a diffuse pattern of laminin deposition below the pial surface which correlated with an abrupt termination of many of the radial glial cells. This along with the pial basement membrane defects, contributed to the abnormal positioning of both early-and late-born neurons. Defects in the inner limiting membrane of the eye were associated with a reduction of laminin a1 demonstrating the involvement of the a-dystroglycan:laminin a1 axis in the disease process. These observations demonstrate for the first time that a reduction in Fkrp influences the ability of tissue-specific forms of a-dystroglycan to direct the deposition of several laminin isoforms in the formation of different basement membranes