Abstract
Congenital muscular dystrophies (CMDs) are characterized by progressive weakness and degeneration of skeletal muscle. In several forms of CMD, abnormal glycosylation of α-dystroglycan (α-DG) results in conditions collectively known as dystroglycanopathies, which are associated with central nervous system involvement. We recently demonstrated that fukutin, the gene responsible for Fukuyama congenital muscular dystrophy, encodes the ribitol-phosphate transferase essential for dystroglycan function. Brain pathology in patients with dystroglycanopathy typically includes cobblestone lissencephaly, mental retardation, and refractory epilepsy; however, some patients exhibit average intelligence, with few or almost no structural defects. Currently, there is no effective treatment for dystroglycanopathy, and the mechanisms underlying the generation of this broad clinical spectrum remain unknown. Here, we analysed four distinct mouse models of dystroglycanopathy: two brain-selective fukutin conditional knockout strains (neuronal stem cell-selective Nestin-fukutin-cKO and forebrain-selective Emx1-fukutin-cKO), a FukutinHp strain with the founder retrotransposal insertion in the fukutin gene, and a spontaneous Large-mutant Largemyd strain. These models exhibit variations in the severity of brain pathology, replicating the clinical heterogeneity of dystroglycanopathy. Immunofluorescence analysis of the developing cortex suggested that residual glycosylation of α-DG at embryonic day 13.5 (E13.5), when cortical dysplasia is not yet apparent, may contribute to subsequent phenotypic heterogeneity. Surprisingly, delivery of fukutin or Large into the brains of mice at E12.5 prevented severe brain malformation in Emx1-fukutin-cKO and Largemyd/myd mice, respectively. These findings indicate that spatiotemporal persistence of functionally glycosylated α-DG may be crucial for brain development and modulation of glycosylation during the fetal stage could be a potential therapeutic strategy for dystroglycanopathy.
Highlights
Post-translational modification refers to the chemical modification of proteins following translation—a process that regulates many functions of the proteins involved
Glycosylation is among the most critical post-translational modifications, and abnormal glycosylation is often associated with human diseases such as congenital muscular dystrophy (CMD)
Cobblestone lissencephaly is characterized by bumpy cortical surfaces and shallow sulci, and previous studies have shown that CMDs accompanied by cobblestone lissencephaly are caused by defective glycosylation of a-dystroglycan (a-DG)
Summary
Post-translational modification refers to the chemical modification of proteins following translation—a process that regulates many functions of the proteins involved. Cobblestone lissencephaly is characterized by bumpy cortical surfaces and shallow sulci, and previous studies have shown that CMDs accompanied by cobblestone lissencephaly are caused by defective glycosylation of a-dystroglycan (a-DG) These types of CMDs are categorized as dystroglycanopathies [2,3], for which there is currently no effective treatment. Mutation of the LARGE gene causes CMD type 1D (MDC1D), which is accompanied by severe mental retardation and brain malformation [22]. Previous studies have suggested that clinical heterogeneity in patients with FCMD can be explained in part by differences in the types of mutations [24], some of which may influence the enzymatic activity of fukutin, the precise mechanism remains unclear. Our findings provide insight regarding the potential for therapeutic intervention during the fetal stage, which may prevent brain malformation in patients with dystroglycanopathy
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