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

•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-MM...

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Veröffentlicht in:Matrix biology 2021-03, Vol.97, p.20-39
Hauptverfasser: 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
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Sprache:eng
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Zusammenfassung:•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.
ISSN:0945-053X
1569-1802
DOI:10.1016/j.matbio.2021.02.003