O.1 Collagen XII as a new disease gene for Bethlem-like myopathy

Bethlem myopathy (BM) is a slowly progressive disorder characterized by contractures and a proximal myopathy, which can be caused by mutations in one of the collagen VI genes (COL6A1, COL6A2, and COL6A3), although genetic heterogeneity is predicted to be as high as 50%. Using whole exome sequencing (WES) we have identified mutations in a novel gene, COL12A1, a member of the FACIT collagens (fibril-associated collagens with interrupted triple helices) in five individuals from two families. In eighteen additional families we have excluded 12 other genes which were considered candidates for causative genes in non-collagen VI BM based on their function, including known binding partners of, and enzymes involved in correct post translational modification, assembly and secretion of collagen VI. Both families carry dominant mutations with a clinical phenotype indistinguishable from classical BM, apart from an intriguing improvement in disease course over time in one of the families and a different pattern of selective muscle involvement on MRI. Family 1 has a single-base substitution that leads to the replacement of one glycine residue in the triple helical domain, breaking the Gly-X-Y repeating pattern, which is known to destabilize the triple helix through a local disruption in hydrogen bonding. Family 2 has a missense mutation which creates a mutant protein with an unpaired cysteine residue. Deficiency at the protein level is confirmed in both families by the intracellular retention of collagen XII in patient dermal fibroblasts. Upregulation of genes associated with the endoplasmic reticulum-associated protein degradation (ERAD) pathway and swollen, dysmorphic rough-ER as determined by electron microscopy in three members of Family 2 lead to the hypothesis that the unfolded protein response (UPR) contributes to the disease pathomechanism in this family. We suggest that the spectrum of causative genes in BM be extended from the COL6A1-A3 genes to include COL12A1.