| Description |
Collagen VI-related muscular dystrophies (COL6-RD) display phenotypic heterogeneity that includes mild Bethlem myopathy (BM), intermediate (INT), and severe Ullrich congenital muscular dystrophy (UCMD) phenotypes. COL6-RD are characterized by mutations within the collagen VI genes (COL6A1, COL6A2, and COL6A3) that lead to improper formation of collagen VI protein. Resulting symptoms may include progressive muscle weakness, joint contractures, loss of ambulation, and premature death. Variation in phenotypic severity is not fully explained by primary collagen VI gene mutations alone, suggesting the presence of genetic modifier loci that control the level of pathogenic response. Previous studies have shown that the gene encoding latent transforming growth factor β binding protein 4 (LTBP4) plays a role in genetically modifying the severity of phenotypes in other muscular dystrophies including sarcoglycanopathy in mice and Duchenne muscular dystrophy (DMD) in humans. We sought to test the hypothesis that LTBP4 is a modifier of clinical severity of COL6-RD. Genotyping of one of the four single nucleotide polymorphisms (SNPs) that define the IAAM haplotype of the LTBP4 gene was performed in a cohort of comprehensively phenotyped COL6-RD patients. The LTBP4 haplotype was determined in 45 individuals with COL6-RD and associated with clinical severity outcomes using chi-squared (χ2) tests. This study provides critical insights into the phenotypic heterogeneity seen in individuals with COL6-RD, helps identify targets for the development of novel gene therapies, and provides an important model for future studies of the molecular pathogenesis of COL6-RD and other forms of muscular dystrophy. |
