Position of Glycine Substitutions in the Triple Helix ofCOL6A1,COL6A2, andCOL6A3is Correlated with Severity and Mode of Inheritance in Collagen VI Myopathies

Abstract

Glycine substitutions in the conserved Gly-X-Y motif in the triple helical domain of collagen VI are the most commonly identified mutations in the collagen VI myopathies including Ullrich congenital muscular dystrophy, Bethlem myopathy, and intermediate phenotypes. We describe clinical and genetic characteristics of 97 individuals with glycine substitutions in the triple helical domain of COL6A1, COL6A2, or COL6A3 and add a review of 97 published cases, for a total of 194 cases. Clinical findings include severe, intermediate, and mild phenotypes even from patients with identical mutations. Intermediate phenotypes were most common, accounting for almost half of patients, emphasizing the importance of intermediate phenotypes to the overall phenotypic spectrum. Glycine substitutions in the triple helical 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 to 15, accounting for only 5% of the triple helical 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.

Bethlem myopathy: long-term follow-up identifies COL6 mutations predicting severe clinical evolution

“…Interestingly, we observed broad clinical variability within the same family ranging from LGMD or congenital myopathy phenotype with no contractures to a more classical phenotype with contractures and weakness 34. Modifier genes or haplotypes have already been described in some other neuromuscular diseases and may also play a role in influencing phenotype presentation in COLVI myopathies 29 25. Clinical examination of other members of the family together with muscle imaging were instrumental in reorienting towards COL6 gene screening, particularly in the three patients with atypical phenotypes.…”

Paternal germline mosaicism in collagen VI related myopathies

“…Possible somatic mosaicism was described for a COL6A1 mutation in the unaffected father of a patient with an intermediate phenotype 9 and very recently, mosaicism was reported in four families with Collagen VI-related disease, as cause of interfamilial phenotypic variability. 13…”

Target resequencing of neuromuscular disease-related genes using next-generation sequencing for patients with undiagnosed early-onset neuromuscular disorders

“…[38][39][40] LGMD is a disease group that shows a high degree of heterogeneity. To date, 31 genes (autosomal dominant: 8 genes; autosomal recessive: 23 genes) have been identified as causative genes of LGMD.…”