Deletion of brain dystroglycan recapitulates aspects of congenital muscular dystrophy

Abstract

Fukuyama congenital muscular dystrophy (FCMD), muscle-eye-brain disease (MEB), and Walker-Warburg syndrome are congenital muscular dystrophies (CMDs) with associated developmental brain defects. Mutations reported in genes of FCMD and MEB patients suggest that the genes may be involved in protein glycosylation. Dystroglycan is a highly glycosylated component of the muscle dystrophin-glycoprotein complex that is also expressed in brain, where its function is unknown. Here we show that brain-selective deletion of dystroglycan in mice is sufficient to cause CMD-like brain malformations, including disarray of cerebral cortical layering, fusion of cerebral hemispheres and cerebellar folia, and aberrant migration of granule cells. Dystroglycan-null brain loses its high-affinity binding to the extracellular matrix protein laminin, and shows discontinuities in the pial surface basal lamina (glia limitans) that probably underlie the neuronal migration errors. Furthermore, mutant mice have severely blunted hippocampal long-term potentiation with electrophysiologic characterization indicating that dystroglycan might have a postsynaptic role in learning and memory. Our data strongly support the hypothesis that defects in dystroglycan are central to the pathogenesis of structural and functional brain abnormalities seen in CMD.

Mechanisms of Disease: congenital muscular dystrophies—glycosylation takes center stage

“…[38][39][40] Admittedly, loss of the entire dystroglycan protein might have effects beyond those caused by defects in its glycosylation, but these data nevertheless support the possibility that all glycosylation defects in the dystroglycanopathies could be centered on dystroglycan. This characterization represents the current state of the literature.…”

Potassium channel Kir4.1 macromolecular complex in retinal glial cells

“…Such mutations also result in structural and physiological changes within the CNS, revealing an important role for the DGC in brain function. For example, a mutant form of a-dystroglycan results in structural anomalies within the brain and prevents the onset of hippocampal LTP (Moore et al, 2002). Dystro-phin mutants also show abnormal electroretinogram (ERG) profiles (Pillers et al, 1999a,b;Dalloz et al, 2003), and the elimination of Dp71 results in the mislocalization of both Kir4.1 and AQP4 in mouse retina (Connors and Kofuji, 2002;Dalloz et al, 2003).…”

Congenital muscular dystrophy. Part II: a review of pathogenesis and therapeutic perspectives

“…Protein o-mannose beta-1,2-N-acetylglucosaminyltransferase (PoMGnT1) that was isolated in 2001 16 , is the first human glycosyltransferase which was found to participate in o-mannosyl glycan synthesis in muscle and brain by adding N-acetylglucosamine to O-linked mannose 16 . soon after, Michele et al 17 and Moore et al 18 suggested that, in addition to PoMGnT1, fukutin and acetylglucosaminyltransferase-like protein (lArGe) may participate in a similar pathway "that ultimately results in transfers of sugar to dystroglycan". In patients with FCMD or MeB disease and in dystrophic mice they demonstrated that the o-glycosylation of alpha-DG, mediated by different glycosyltransferases, is essential for muscle and brain development and functions.…”

“…At last, in 2002 two works from Campbells' research group at the Iowa University 17,18 demonstrated that patients with MeB and FCMD, who carry mutant PoMGnT1 and fukutin genes, respectively, had an abnormal hypo- FCMD: Fukuyama congenital muscular dystrophy; lGMD: limb girdle muscular dystrophy; MDC: muscular dystrophy, congenital; MeB: muscle-eye-brain; PoMGnT1: protein o-manose beta1,2-N-acetylglucosaminyltransferase; WWs: Walker-Warburg syndrome.…”

“…Dystroglycan glycosylation is highly conserved during evolution. The covalently addiction of sugar chains (glycans), forming a glycoprotein, induces a modification that increases the availability of the protein for ligand interaction with laminin, agrin and perlecan in skeletal muscle, as well as with laminin and neurexin in the brain [11][12][13][14][15][16][17][18] . The glycoproteins act as biosignals for cell-cell communication, intracellular signaling, protein folding, and targeting of proteins within cells [11][12][13][14][15] .…”