Observations of dystrophic epidermolysis bullosa patients with collagen VII NC2 truncation provide new insights into anchoring fibril assembly.

Type VII collagen (C7) assembles into anchoring fibrils (AF) which are basement membrane zone (BMZ) structures that reinforce dermal-epidermal cohesion. Mutations in COL7A1, which encodes C7, cause dystrophic epidermolysis bullosa (DEB), a blistering disorder characterized by skin fragility. C7 consists of a central collagenous domain flanked by non-collagenous NC1 and NC2 regions. During AF assembly, C-proteinase-mediated cleavage of the NC2 domain enables anti-parallel dimer formation, followed by C7 lateral association into mature, banded AFs that loop through the dermis to anchor the epidermis. Here, we report two DEB patients expressing near full-length C7 truncated just proximal to the C-proteinase cleavage site (amino acids 2814-2843), which precludes anti-parallel dimerization. Despite this, electron microscopy revealed abundant, banded AFs, consistent with lateral association, but the fibrils failed to loop and reinsert into the BMZ. These findings demonstrate that C7 lateral association can occur independently of anti-parallel dimer formation. This work also highlights the importance of AF looping in maintaining skin integrity and how specific COL7A1 mutations may impact fibril architecture and clinical phenotype.