An SNP variant MT1-MMP with a defect in its collagenolytic activity confers the fibrotic phenotype of Dupuytren's Disease

Itoh, Y.; Ng, M.; Wiberg, A.; Inoue, K.; Hirata, N.; Paiva, K. B.; Ito, N.; Dzobo, K.; Sato, N.; Gifford, V.; Fijita, Y.; Inada, M.; Furniss, D.

doi:10.1101/2020.06.09.142513

bioRxiv · 10.1101/2020.06.09.142513

An SNP variant MT1-MMP with a defect in its collagenolytic activity confers the fibrotic phenotype of Dupuytren's Disease

Itoh, Y.·Ng, M.·Wiberg, A.·Inoue, K.·Hirata, N.·Paiva, K. B.·Ito, N.·Dzobo, K.·Sato, N.·Gifford, V.·Fijita, Y.·Inada, M.·Furniss, D.

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Abstract

Dupuytrens 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.

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Itoh, Y., Ng, M., Wiberg, A., Inoue, K., Hirata, N., Paiva, K. B., Ito, N., Dzobo, K., Sato, N., Gifford, V., Fijita, Y., Inada, M., Furniss, D.. 2020-06-12. An SNP variant MT1-MMP with a defect in its collagenolytic activity confers the fibrotic phenotype of Dupuytren's Disease. https://doi.org/10.1101/2020.06.09.142513

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