Journal article
Functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype
IJHM De Vos, EY Tao, SLM Ong, JL Goggi, T Scerri, GR Wilson, CGM Low, ASW Wong, D Grussu, APA Stegmann, M Van Geel, R Janssen, DJ Amor, M Bahlo, NR Dunn, TJ Carney, PJ Lockhart, BJ Coull, MAM Van Steensel
Human Molecular Genetics | OXFORD UNIV PRESS | Published : 2018
DOI: 10.1093/hmg/ddy168
Abstract
Winchester syndrome (WS, MIM #277950) is an extremely rare autosomal recessive skeletal dysplasia characterized by progressive joint destruction and osteolysis. To date, only one missense mutation in MMP14, encoding the membrane-bound matrix metalloprotease 14, has been reported in WS patients. Here, we report a novel hypomorphic MMP14 p.Arg111His (R111H) allele, associated with a mitigated form of WS. Functional analysis demonstrated that this mutation, in contrast to previously reported human and murine MMP14 mutations, does not affect MMP14's transport to the cell membrane. Instead, it partially impairs MMP14's proteolytic activity. This residual activity likely accounts for the mitigated..
View full abstractGrants
Awarded by Australian Government
Funding Acknowledgements
This work was supported by the Skin Research Institute of Singapore (to M.A.M.v.S. and E.Y.T.), the Biomedical Research Council Singapore (to M.A.M.v.S.), the Agency for Science, Technology and Research (A*STAR Research Attachment Programme to I.J.H.M.d.V.), the Wellcome Trust (DGEM to M.A.M.v.S. and B.J.C.), Tenovus Scotland (T15/22 and T15/62 to M.A.M.v.S. and B.J.C.), the Victorian Government's Operational Infrastructure Support Program, and the Australian Government (NHMRC Senior Research Fellowship 110297 and NHMRC Program Grant 1054618 to M.B., NHMRC Career Development Fellowship GNT1032364 to P.J.L.). Funding to pay the Open Access publication charges for this article was provided by COAF (Charities Open Access Fund) awarded to the University of Dundee.