Functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype

Ivo J. H. M. de Vos, Evelyn Yaqiong Tao, Sheena Li Ming Ong, Julian L. Goggi, Thomas Scerri, Gabrielle R. Wilson, Chernis Guai Mun Low, Arnette Shi Wei Wong, Dominic Grussu, Alexander P. A. Stegmann, Michel van Geel, Renske Janssen, David J. Amor, Melanie Bahlo, Norris R. Dunn, Thomas J. Carney, Paul J. Lockhart, Barry Coull, Maurice van Steensel

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    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 phenotype observed in our patients. Based on our observations as well as previously published data, we hypothesize that MMP14’s catalytic activity is the prime determinant of disease severity. Given the limitations of our in vitro assays in addressing the consequences of MMP14 dysfunction, we generated a novel mmp14a/b knockout zebrafish model. The fish accurately reflected key aspects of the WS phenotype including craniofacial malformations, kyphosis, short-stature and reduced bone density due to defective collagen remodeling. Notably, the zebrafish model will be a valuable tool for developing novel therapeutic approaches to a devastating bone disorder.
    Original languageEnglish
    Article numberddy168
    Pages (from-to)2775-2788
    Number of pages14
    JournalHuman Molecular Genetics
    Issue number16
    Early online date8 May 2018
    Publication statusPublished - 15 Aug 2018

    ASJC Scopus subject areas

    • Molecular Biology
    • Genetics
    • Genetics(clinical)


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