Position of glycine substitutions in the triple helix of COL6A1, COL6A2, and COL6A3 is correlated with severity and mode of inheritance in collagen vi myopathies

摘要

Glycine substitutions in the conserved Gly-X-Y motif in the triple helical (TH) domain of collagen VI are the most commonly identified mutations in the collagen VI myopathies including Ullrich congenital muscular dystrophy, Bethlem myopathy, and intermediate (INT) phenotypes. We describe clinical and genetic characteristics of 97 individuals with glycine substitutions in the TH domain of COL6A1, COL6A2, or COL6A3 and add a review of 97 published cases, for a total of 194 cases. Clinical findings include severe, INT, and mild phenotypes even from patients with identical mutations. INT phenotypes were most common, accounting for almost half of patients, emphasizing the importance of INT phenotypes to the overall phenotypic spectrum. Glycine substitutions in the TH domain are heavily clustered in a short segment N-terminal to the 17th Gly-X-Y triplet, where they are acting as dominants. The most severe cases are clustered in an even smaller region including Gly-X-Y triplets 10-15, accounting for only 5% of the TH domain. Our findings suggest that clustering of glycine substitutions in the N-terminal region of collagen VI is not based on features of the primary sequence. We hypothesize that this region may represent a functional domain within the triple helix. Glycine substitutions in the Gly-X-Y motif in the triple helical domain of COL6A1, COL6A2, or COL6A3 are the most commonly identified mutations in Ullrich congenital muscular dystrophy and Bethlem myopathy. We describe clinical and genetic characteristics of 97 individuals with glycine substitutions in this region including clustering of these mutations in a short segment N-terminal to the 17th Gly-X-Y triplet which is associated with increased severity. We hypothesize that this region may represent a functional domain within the triple helix. Published 2013. Wiley Periodicals, Inc. *This article is a U.S. Government work and is in the public domain in the USA.