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

Abstract

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 ␣-dystroglycan and its inability to effectively bind extracellular matrix ligands such as laminin ␣2. However, ␣-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 ␣-chain expression in the cerebral cortex and eye of our FKRP knock-down mouse (FKRP KD ). These mice showed a marked disturbance in the deposition of laminin ␣-chains including ␣1, ␣2, ␣4, and ␣5, although only laminin ␣1-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 ␣1 demonstrating the involvement of the ␣-dystroglycan:laminin ␣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 ␣-dystroglycan to direct the deposition of several laminin isoforms in the formation of different basement membranes.

Biochemical and biophysical changes underlie the mechanisms of basement membrane disruptions in a mouse model of dystroglycanopathy

“…Recently, it was suggested that laminin deposition is altered within the cerebral cortex of FKRP knock-down mice (Ackroyd et al , 2011). The laminin staining pattern in FKRP knock-down mice is similar to that observed for POMGnT1 knockout mice (Hu et al , 2007).…”

“…Moreover, the inner limiting membrane (ILM), a BM of the retina is disrupted (Ackroyd et al, 2011;Hu et al, 2010;Lee et al, 2005;Satz et al, 2008). Additionally, DG (Williamson et al, 1997), POMT1 (Willer et al, 2004), and POMT2 (Hu et al, 2011a) null embryos die due to disruptions in Reichert’s membrane, an extra-embryonic BM.…”

Evidence of early defects in Cajal–Retzius cell localization during brain development in a mouse model of dystroglycanopathy

“…To investigate the pathogenesis of the dystroglycanopathies further, we previously generated a mouse model of dystroglycanopathy which has a deficiency in fukutin-related protein (FKRP KD ). This mouse recapitulates some of the features of MEB; displaying a profound reduction in the glycosylation of alpha dystroglycan at the pial basement membrane, associated with basement membrane defects and a neuronal migration disorder [29,30]. In the dystroglycanopathies, this brain phenotype has been attributed to the inability of the radial glial end feet to maintain integrity of the pial basement membrane during the period of rapid cortical expansion; a process considered central to the neuronal migration defect in these disorders [31,32].…”

An irish case of limb‐girdle muscular dystrophy 2I with structural eye involvement

“…FKRP plays a role in glycosylation of α‐dystroglycan, an extracellular glycoprotein that mediates deposition of basement membranes by binding to various components such as laminin, perlecan, biglycan, agrin, and neurexin . Mutations in FKRP result in hypoglycosylation and downregulation of α‐dystroglycan and lead to disruption of basement membrane integrity.…”

“…We hypothesize that the lens capsule, an uninterrupted basement membrane surrounding the ocular lens, became defective in this patient, resulting in capsular opacification and cataract formation. Interestingly, it was demonstrated in an animal model that a reduced FKRP influences the ability of tissue‐specific (eye and brain) forms of α‐dystroglycan to direct deposition of laminin isoforms to form different basement membranes . Notably, immunohistochemical analysis of muscle tissue from the patient demonstrated normal merosin (laminin‐2).…”