Collagen VI Muscle Disorders: Mutation Types, Pathogenic Mechanisms and Approaches to Therapy

Mutations in the genes encoding the major collagen VI isoform, COL6A1, COL6A2 and COL6A3, are responsible for the muscle disorders Bethlem myopathy and Ullrich congenital muscular dystrophy. These disorders form a disease spectrum from mild to severe. Dominant and recessive mutations are found along the entire spectrum and the clinical phenotype is strongly influenced by the way mutations impede collagen VI protein assembly. Most mutations are in the triple helical domain, towards the N-terminus and they compromise microfibril assembly. Some mutations are found outside the helix in the C- and N-terminal globular domains, but because these regions are highly polymorphic it is difficult to discriminate mutations from rare benign changes without detailed structural and functional studies. Collagen VI deficiency leads to mitochondrial dysfunction, deficient autophagy and increased apoptosis. Therapies that target these consequences have been tested in mouse models and some have shown modest efficacy in small human trials. Antisense therapies for a common mutation that introduces a pseudoexon show promise in cell culture but haven't yet been tested in an animal model. Future therapeutic approaches await new research into how collagen VI deficiency signals downstream consequences.