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

Mutations in fukutin-related protein (FKRP) are responsible for a common group 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 alpha-dystroglycan and its inability to effectively bind extracellular matrix ligands such as laminin alpha 2. However, alpha-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 alpha-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 alpha-chains including alpha 1, alpha 2, alpha 4, and alpha 5, although only laminin alpha 1- and gamma 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 alpha 1 demonstrating the involvement of the alpha-dystroglycan: laminin alpha 1 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 alpha-dystroglycan to direct the deposition of several laminin isoforms in the formation of different basement membranes.