Journal article
A common SNP risk variant MT1-MMP causative for Dupuytren’s Disease has a specific defect in collagenolytic activity
- Abstract:
- 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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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- Files:
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(Preview, Accepted manuscript, 9.5MB, Terms of use)
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- Publisher copy:
- 10.1016/j.matbio.2021.02.003
Authors
- Publisher:
- Elsevier
- Journal:
- Matrix Biology More from this journal
- Volume:
- 97
- Pages:
- 20-39
- Publication date:
- 2021-02-13
- Acceptance date:
- 2021-02-10
- DOI:
- ISSN:
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0174-173X
- Language:
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English
- Keywords:
- Pubs id:
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1161093
- Local pid:
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pubs:1161093
- Deposit date:
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2021-02-10
Terms of use
- Copyright holder:
- Elsevier
- Copyright date:
- 2021
- Rights statement:
- © 2021 Elsevier B.V. All rights reserved.
- Notes:
- This is the accepted manuscript version of the article. The final version is available online from Elsevier at: https://doi.org/10.1016/j.matbio.2021.02.003
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