RT Journal Article
SR Electronic
T1 An SNP variant MT1-MMP with a defect in its collagenolytic activity confers the fibrotic phenotype of Dupuytren’s Disease
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.06.09.142513
DO 10.1101/2020.06.09.142513
A1 Yoshifumi Itoh
A1 Michael Ng
A1 Akira Wiberg
A1 Katsuaki Inoue
A1 Narumi Hirata
A1 Katiucia Batista Silva Paiva
A1 Noriko Ito
A1 Kim Dzobo
A1 Nanami Sato
A1 Valentina Gifford
A1 Yasuyuki Fujita
A1 Masaki Inada
A1 Dominic Furniss
YR 2020
UL http://biorxiv.org/content/early/2020/06/12/2020.06.09.142513.abstract
AB 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.