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Title: Functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype
Authors: de Vos, Ivo J. H. M.
Goggi, Julian L.
Wilson, Gabrielle R.
Stegmann, Alexander P. A.
Amor, David J.
Dunn, Norris Ray
Carney, Thomas James
Lockhart, Paul J.
Coull, Barry J.
van Steensel, Maurice A. M.
Tao, Evelyn Yaqiong
Ong, Sheena Li Ming
Scerri, Thomas
Low, Chernis Guai Mun
Wong, Arnette Shi Wei
Grussu, Dominic
van Geel, Michel
Janssen, Renske
Bahlo, Melanie
Keywords: Alleles
Issue Date: 2018
Source: de Vos, I. J. H. M., Tao, E. Y., Ong, S. L. M., Goggi, J. L., Scerri, T., Wilson, G. R., . . . van Steensel, M. 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), 2775-2788. doi:10.1093/hmg/ddy168
Series/Report no.: Human Molecular Genetics
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.
ISSN: 0964-6906
DOI: 10.1093/hmg/ddy168
Rights: © 2018 The Author(s). Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:LKCMedicine Journal Articles

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