Post-translational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies

Area of Science:

• Biochemistry
• Neuroscience
• Genetics

Background:

• Muscle eye brain disease (MEB) and Fukuyama congenital muscular dystrophy (FCMD) are congenital muscular dystrophies characterized by similar brain malformations.
• The genes responsible, POMGnT1 (MEB) and fukutin (FCMD), are homologous to glycosyltransferases, suggesting a role in protein modification.

Purpose of the Study:

• To investigate the functional impact of mutations in MEB and FCMD on alpha-dystroglycan.
• To elucidate the pathogenic mechanism underlying muscular dystrophy and brain abnormalities in these diseases.

Main Methods:

• Analysis of alpha-dystroglycan glycosylation and binding activity in MEB and FCMD patients.
• Utilizing the myodystrophy (myd) mouse model to study the effects in vivo.
• Examining neuronal migration and basal lamina integrity in the central nervous system of myd mice.

Main Results:

• Hypoglycosylation of alpha-dystroglycan in MEB and FCMD patients abolishes its binding to ligands like laminin, neurexin, and agrin.
• This hypoglycosylation and functional disruption are replicated in the muscle and brain of myd mice.
• Myd mice exhibit abnormal neuronal migration and disrupted basal lamina, indicating dystroglycan's role in brain development and protein targeting.

Conclusions:

• At least three mammalian genes converge in a post-translational pathway for dystroglycan biosynthesis.
• Abnormal dystroglycan-ligand interactions are central to the pathogenesis of muscular dystrophies with brain abnormalities.
• Dystroglycan plays a critical role in targeting proteins to functional sites in the brain via extracellular matrix interactions.