Dystroglycanopathies: clinical manifestations and genetics and molecular basis of the muscular dystrophies caused by defective glycosylation of α-dystroglycan
Keywords:
Muscular dystrophy, dystroglycanopathies, α-dystroglycan, glycosyltransferase, glycosylationAbstract
In general, human muscular dystrophies are caused by mutations in genes encoding for key proteins of the muscular tissue. A specific group of muscular dystrophies is related to mutations in genes encoding for members of the dystrophin-associated protein complex (DAPC). The DAPC links the extracellular matrix with the actin-based cytoskeleton, conferring thereby stability to the sarcolemma during cycles of muscular contraction/relaxation. A pivotal component of this assembly is dystroglycan, a protein encoded by the DAG1 gene, which is post-translationally processed into two subunits; α- and β-dystroglycan. α-dystroglycan (α-DG) is an extracellular
protein that interacts with the extracellular protein laminin, while β-dystroglycan (β-DG) is a transmembranal protein that associates with both α-DG and actin. Therefore, α- and β-DG communicate the extracellular matrix with the actin-based cytoskeleton. α-DG requires to be glycosylated to properly interact with laminin, and such posttranslational modification has biological relevance because a series of muscular dystrophies called «dystroglycanopathies» are caused by defective α-DG glycosylation. Primary dystroglycanopathies are due to homozygous mutations in the DAG1 gene, while secondary dystroglycanopathies are caused by mutations in at least 15 different genes involved in the α-DG glycosylation pathway. The most character- ized dystroglycanopathies include the Walker-Warburg syndrome, muscle-eye-brain disease, congenital muscular dystrophies 1C and 1D, and limb-girdle muscular dystrophy. In this review, we describe the clinical aspects of the different dystroglycanopatheis and present an updated view of the genetic and molecular mechanisms underlying these pathologies. Finally, we de- scribe the animal models and therapeutic strategies designed to fight dystroglycanopathies.
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