 I am Dr. Russell Butterfield from the Department of Neurology and Pediatrics at the University of Utah. I will be presenting our paper, The Position of Glycine Substitutions in the Triple Helix of Call 6A1, Call 6A2, and Call 6A3 determines severity and mode of inheritance in the collagen 6 myopathies. This work is a collaboration between the Utah Genome Center led by Dr. Robert Weiss and Dr. Karsten Bonaman's group at NINDS, the National Institute of Health. The collagen 6 myopathies are among the most common congenital muscular dystrophies and are characterized by a combination of weakness with distal joint laxity and joint contractures in the more severe phenotype or congenital muscular dystrophy. Symptoms are onset in the early neonatal period and lead to respiratory insufficiency and loss of ambulation before age 12. In the milder form, Bethlehem myopathy symptoms are onset in late childhood and early adolescence and ambulation is maintained well into adulthood. Intermediate phenotypes are increasingly recognized, however, the reasons for the wide disparity in clinical symptoms are poorly understood. In this paper, we present the clinical and genetic characteristics of a combined series of 97 patients with substitutions of the conserved glycine residues in the triple helical domain of the collagen 6 genes and include a cohort of 97 previously published patients with similar mutations. The position of the glycine mutation in all 194 patients in our series is outlined in the figure. The cysteine residue at the 17th glyxy triplet marked by the dashed line is an important structural landmark in collagen 6 with 89% of glycine substitutions clustered and terminal to this point. This segment of the triple helix is unencumbered by associations with other chains during the assembly process and may define a functional domain within the segment of the triple helix. Position of the glycine substitutions in the triple helix determines dominance, recessive cases are rare and all are in the C-terminal end of the triple helix while the N-terminal glycine substitutions are dominant. This is an important distinction as gene replacement is a potential therapeutic avenue for recessive mutations while allele specific knockdown is a potential therapeutic avenue for the dominant mutations. Within the region N-terminal to the 17th triplet, PACE et al. in 2008 proposed a critical region spanning triplets 10 to 15 marked here by an orange bar. This region is correlated with a more severe disruption of assembly and increased clinical severity. In our cohort, 59% of glycine substitutions occur in this critical region accounting for only 5% of the length of the triple helical domain. To determine whether genotype could predict the severity of clinical symptoms we grouped patients according to clinical severity and location of the glycine substitution within the triple helical domain. Early severe ulric congenital muscary distro-free patients are the most severe group and these patients never walk. Typical ulric congenital muscary distro-free patients achieve independent ambulation with significant impairment and lose ambulation by age 12. In the intermediate ulric congenital muscary distro-free group patients achieve independent ambulation and maintain it beyond age 12 but often lose it before adulthood and have significant gait impairment. The mildest subgroup, Bethlehemiopathy, are ambulatory into adulthood with only minor impairments in gait. Intermediate ulric congenital muscary distro-free cases were the most common accounting for 40% of patients emphasizing the air importance in the clinical spectrum beyond the classically defined syndromes ulric congenital muscary distro-free and Bethlehemiopathy. As shown in the figure clinical severity was correlated with location of the glycine substitution in the triple helix. Almost half of patients with glycine substitutions in the critical region have severe phenotypes while only a quarter of patients with glycine substitutions outside the critical region have severe phenotypes. We hypothesize that this region may represent a functional domain within the triple helix. It has been proposed that the 30 nanometer segment at the amino terminal end of the triple helical domain containing the critical region marked here in red forms a loop around the end terminal domain of the adjacent tetramer during microfiber formation. Glycine substitution in this region may result in mutant tetramers that are unable to form normal associations with adjacent end terminal globular domains. We hope that you enjoy reading the paper. We thank the patients and families for their participation and our collaborators for their help in performing the study. Please contact us for additional information, discussion, or questions.