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

De Vos, Ivo J.H.M. and Tao, Evelyn Yaqiong and Ong, Sheena Li Ming and Goggi, Julian L. and Scerri, Thomas and Wilson, Gabrielle R. and Low, Chernis Guai Mun and Wong, Arnette Shi Wei and Grussu, Dominic and Stegmann, Alexander P.A. and Van Geel, Michel and Janssen, Renske and Amor, David J. and Bahlo, Melanie and Dunn, Norris R. and Carney, Thomas J. and Lockhart, Paul J. and Coull, Barry J. and Van Steensel, Maurice A.M. (2018) Functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype. Human Molecular Genetics, 27 (16). pp. 2775-2788. ISSN 0964-6906

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 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 owing to defective collagen remodeling. Notably, the zebrafish model will be a valuable tool for developing novel therapeutic approaches to a devastating bone disorder.