Fig. 8: Mapping UCMD and Bethlem myopathy pathogenic mutations on the microfibril structure.

a Frequency plots of missense variants from the HGMD database reported to be disease-causing in collagen VI α1, α2 and α3 chains. The frequency of occurrence of variants on any given amino acid is shown above the domain schematics of collagen VI, approximately to scale, showing in which domains the variants occur. The number of triangles on the y-axis corresponds to the frequency of the occurrence of a mutation on any amino acid. There is a hotspot of Glycine mutations at the N-terminal end of the collagenous region in each of the α-chains^35,36. b A composite density map of the collagen VI double bead is shown, coloured blue for the N-terminal domains and red for the C-terminal domains. The high-frequency Glycine mutations in the collagenous region are coloured in pink, which fall in the collagenous region that traverses the bead region. Above is a model of the microfibril, with connecting N- and C-terminal regions numbered, showing that the bead is compiled from multiple collagen VI monomers. c The hydrophobic residues in the core of the trimeric coiled coil region show residues α2 V594 and V598, where variants that may be pathogenic can occur. d Variants D835E and D905Y in the (α1)C2 domain, which correlate with the risk of spontaneous Coronary Artery Dissection, are shown in grey in a tetramer interface within the bead. e Three Bethlem myopathy pathogenic variants in the (α2)C2 domain^71,72 localise to the domain interfaces between the (α3)C1 (R830W and R843W) and (α1)C2 (W1017R) domains, shown as yellow spheres. c–e are coloured by chain (α1—green, α2—cyan and α3—magenta), with symmetry-related chains shown in darker shades.