A common SNP risk variant MT1-MMP causative for Dupuytren's disease has a specific defect in collagenolytic activity

Dupuytren's Disease (DD) is a common fibroproliferative disease of the palmar fascia. We previously identified a causal association with a non-synonymous variant (rs1042704, p.D273N) in MMP14 (encoding MT1-MMP). In this study, we investigated the functional consequences of this variant, and demonstrated that the variant MT1-MMP (MT1-N-273) exhibits only 17% of cell surface collagenolytic activity compared to the ancestral enzyme (MT1-D-273). Cells expressing both MT1-D-273 and MT1-N-273 in a 1:1 ratio, mimicking the heterozygous state, possess 38% of the collagenolytic activity compared to the cells expressing MT1-D-273, suggesting that MT1-N-273 acts in a dominant negative manner. Consistent with the above observation, patient-derived DD myofibroblasts with the alternate allele demonstrated around 30% of full collagenolytic activity detected in ancestral G/G genotype cells, regardless of the heterozygous (G/A) or homozygous (A/A) state. Small angle X-ray scattering analysis of purified soluble Fc-fusion enzymes allowed us to construct a 3D-molecular envelope of MT1-D-273 and MT1-N-273, and demonstrate altered flexibility and conformation of the ectodomains due to D273 to N substitution. Taking together, rs1042704 significantly reduces collagen catabolism in tissue, which tips the balance of homeostasis of collagen in tissue, contributing to the fibrotic phenotype of DD. Since around 30% of the worldwide population have at least one copy of the low collagenolytic alternate allele, further investigation of rs1042704 across multiple pathologies is needed. (C) 2021 Elsevier B.V. All rights reserved.

Automated summary

The variant rs1042704 in the MMP14 gene was found to significantly reduce collagen catabolism in Dupuytren's Disease, leading to a fibrotic phenotype. This variant alters cell surface collagenolytic activity and acts in a dominant negative manner, affecting the balance of collagen homeostasis in tissue.