Segmented ring-mesh model of glycosaminoglycan chains based on the 3D analysis of normal individual and musculocontractural Ehlers–Danlos syndrome skin using scanning transmission electron microscopy

Collagen fibrils in the dermis are bundled by glycosaminoglycan (GAG) chains of decorin, which contribute to its strength. The three-dimensional structure of collagen fibrils and GAG chains has been discussed on the basis of observations and experiments. This study uses scanning transmission electron microscope (STEM) tomography with high Z-axis resolution to analyze the three-dimensional structure of GAG chains in the dermis from a healthy individual and a patient with musculocontractural Ehlers-Danlos syndrome caused by pathogenic variants in CHST14 (mcEDS-CHST14). This observation revealed that the dermis from a healthy individual featured multiple GAG chains that wrapped around collagen fibrils and formed incomplete ring structures. However, in the dermis from a patient with mcEDS-CHST14, GAG chains were linear and did not form rings. Based on the relationship between collagen fibrils and GAG chains, we suggest the three-dimensional structure of normal GAG chains in a new model named the 'segmented ring-mesh model'. The interactions between collagen fibrils and GAG chains in this model also apply to the dermis of mcEDS-CHST14 patients, in which the GAG chain composition changes to become CS-rich and more linear. This change leads to an increased inter-fibrillar space, which inhibits the dense packing of collagen fibrils. These findings suggest that this phenomenon contributes to the skin fragility observed in mcEDS-CHST14 patients. Our study suggests the 'segmented ring-mesh model' of GAG chains is essential for the dense packing of collagen fibrils in normal dermis. STEM tomography is highly effective in analyzing the three-dimensional structure of collagen fibrils and GAG chains.