An SNP variant MT1-MMP with a defect in its collagenolytic activity confers the fibrotic phenotype of Dupuytren’s Disease
An SNP variant MT1-MMP with a defect in its collagenolytic activity confers the fibrotic phenotype of Dupuytren’s Disease
Abstract Dupuytren’s Disease (DD) is a common fibroproliferative disease of the palmar fascia. We previously identified a strong association with a non-synonymous variant (rs1042704, pD273N) in MMP14 (encoding MT1-MMP). 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 this hypothesis, patient-derived DD myofibroblasts expressing MT1-N273 demonstrated around 30% of full collagenolytic activity regardless of the heterozygous or homozygous state. 3D-molecular envelope modelling using small angle X-ray scattering demonstrated altered positioning of the catalytic domain within dimeric molecules. Taken together, our data suggest that rs1042704 directly contributes to the fibrotic phenotype of DD.
Paiva Katiucia Batista Silva、Wiberg Akira、Hirata Narumi、Dzobo Kim、Sato Nanami、Inada Masaki、Ng Michael、Furniss Dominic、Gifford Valentina、Fujita Yasuyuki、Inoue Katsuaki、Ito Noriko、Itoh Yoshifumi
Kennedy Institute of Rheumatology, NDORMS, University of Oxford||Department of Anatomy, Institute of Biomedical Sciences, University of S?o PauloBotnar Research Centre, NDORMS, University of OxfordKennedy Institute of Rheumatology, NDORMS, University of Oxford||Department of Biotechnology and Life Science, Tokyo University of Agriculture and TechnologyKennedy Institute of Rheumatology, NDORMS, University of OxfordKennedy Institute of Rheumatology, NDORMS, University of Oxford||Institute for Genetic Medicine, Division of Molecular Oncology, Hokkaido UniversityDepartment of Biotechnology and Life Science, Tokyo University of Agriculture and TechnologyBotnar Research Centre, NDORMS, University of OxfordBotnar Research Centre, NDORMS, University of OxfordKennedy Institute of Rheumatology, NDORMS, University of OxfordInstitute for Genetic Medicine, Division of Molecular Oncology, Hokkaido UniversityDiamond Light Source, Harwell Science & Innovation CampusKennedy Institute of Rheumatology, NDORMS, University of OxfordKennedy Institute of Rheumatology, NDORMS, University of Oxford
基础医学分子生物学遗传学
Paiva Katiucia Batista Silva,Wiberg Akira,Hirata Narumi,Dzobo Kim,Sato Nanami,Inada Masaki,Ng Michael,Furniss Dominic,Gifford Valentina,Fujita Yasuyuki,Inoue Katsuaki,Ito Noriko,Itoh Yoshifumi.An SNP variant MT1-MMP with a defect in its collagenolytic activity confers the fibrotic phenotype of Dupuytren’s Disease[EB/OL].(2025-03-28)[2025-04-26].https://www.biorxiv.org/content/10.1101/2020.06.09.142513.点此复制
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