A missense mutation (C667F) in beta-dystroglycan results in reduced dystroglycan protein levels leading to myopathy and destabilization of the blood-brain and blood-retinal barrier protein network

Abstract

Dystroglycan (DG) is a glycoprotein and extracellular matrix receptor consisting of an -DG and a {beta}-DG subunit encoded by the gene DAG1. A homozygous missense mutation (c.2006G>T), resulting in an amino acid substitution (p.Cys669Phe) in the extracellular domain of {beta}-DG, causes severe Muscle-Eye-Brain disease with multicystic leukodystrophy. To investigate the mechanisms underlying the severe human pathology, we generated a mouse model of this primary dystroglycanopathy. We find that homozygous mutant mice show no obvious abnormalities during development and reach mature adulthood. However, - and {beta}-DG protein levels are significantly downregulated in muscle and brain of homozygous mutant mice. The mutant mice show a form of myopathy with late-onset and not fully penetrant histopathological changes in skeletal muscle and are impaired in their performance on an activity wheel. The brain and eyes of the homozygous mutant mice appear to be structurally normal, but the localization of mutant {beta}-DG is altered in the glial perivascular endfeet (PVE) at the blood-brain- and blood-retina barrier resulting in a perturbed protein composition in the PVE. In conclusion, the mouse model of the C669F {beta}-DG mutation does not seem to recapitulate the severe developmental phenotypes observed in human patients but represents a novel and highly valuable tool to study the impact of {beta}-DG functional changes at the molecular level and to gain insight into the pathogenesis of primary dystroglycanopathies.