Novel mutations in collagen VI genes: Expansion of the Bethlem myopathy phenotype

Objective: To investigate the molecular basis of autosomal dominant limb-girdle muscular dystrophy (ADLGMD) in three large new families. Methods and Results: Genome-wide linkage was performed to show that the causative gene in all three families localized to chromosome 21q22.3 (Zmax = 10.3; θ = 0). This region contained the collagen VI α1 and α2 genes, which have been previously shown to harbor mutations causing a relatively mild congenital myopathy with contractures (Bethlem myopathy). Screening of the collagen VI α1 and α2 genes revealed novel, causative mutations in each family (COL6A1-K121R, G341D; COL6A2-D62ON); two of these mutations were in novel regions of the proteins not previously associated with disease. Collagen VI is a ubiquitously expressed component of connective tissue; however, both limb-girdle muscular dystrophy and Bethlem myopathy patients show symptoms restricted to skeletal muscle. To address the muscle-specific symptoms resulting from collagen VI mutations, the authors studied three patient muscle biopsies at the molecular level (protein expression). A marked reduction of laminin β1 protein in the myofiber basal lamina in all biopsies was found, although this protein was expressed normally in the neighboring capillary basal laminae. Conclusions: The authors' studies widen the clinical spectrum of Bethlem myopathy and suggest collagen VI etiology should be investigated in dominant limb-girdle muscular dystrophy. The authors hypothesize that collagen VI mutations lead to muscle-specific defects of the basal lamina, and may explain the muscle-specific symptoms of Bethlem and limb-girdle muscular dystrophy patients with collagen VI mutations.