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

• Published in: Matrix biology Vol. 97; pp. 20 - 39
• Main Authors: Itoh, Yoshifumi, Ng, Michael, Wiberg, Akira, Inoue, Katsuaki, Hirata, Narumi, Paiva, Katiucia Batista Silva, Ito, Noriko, Dzobo, Kim, Sato, Nanami, Gifford, Valentina, Fujita, Yasuyuki, Inada, Masaki, Furniss, Dominic
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.03.2021; Elsevier Science Ltd
• Subjects: Alleles; Animals; Cell surface; Chlorocebus aethiops; Collagen; Collagen - metabolism; Collagen degradation; Conformation; COS Cells; Dupuytren Contracture - genetics; Dupuytren Contracture - metabolism; Dupuytren's disease; Fascia; Genotypes; Homeostasis; Humans; Matrix Metalloproteinase 14 - chemistry; Matrix Metalloproteinase 14 - genetics; Matrix Metalloproteinase 14 - metabolism; Mimicry; Models, Molecular; MT1-MMP; Phenotypes; Polymorphism, Single Nucleotide; Population genetics; Protein Conformation; Protein Domains; rs1042704; Scattering, Small Angle; SNP; X-Ray Diffraction; X-ray scattering; DD; NGFR; TIMP-2; GWAS; Collagen degradation; ECM; SAXS; MMP; MT1-MMP; rs1042704; Dupuytren's disease; SNP; Hpx domain
• ISSN: 0945-053X; 1569-1802
• DOI: 10.1016/j.matbio.2021.02.003

•Previously we identified a causal association of Dupuytren's Disease (DD) with a non-synonymous SNP variant (rs1042704, p.D273N) of MT1-MMP.•We discovered that this SNP variant MT1-MMP (MT1-N273) exhibits only 17% of cell surface collagenolytic activity compared to the ancestral form of MT1-MMP (MT1-D273).•DD patients myofibroblasts with heterozygous (G/A) and homozygous (A/A) SNP genotypes exhibited around 30% of collagen degrading activities in comparison to cells with wild-type (G/G) genotype.•Low collagenolytic activity of the SNP would contribute to the fibrotic phenotype of DD. 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-N273) exhibits only 17% of cell surface collagenolytic activity compared to the ancestral enzyme (MT1-D273). Cells expressing both MT1-D273 and MT1-N273 in a 1:1 ratio, mimicking the heterozygous state, possess 38% of the collagenolytic activity compared to the cells expressing MT1-D273, suggesting that MT1-N273 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-D273 and MT1-N273, 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.