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dc.contributor.authorde Vos, IJHM
dc.contributor.authorTao, EY
dc.contributor.authorOng, SLM
dc.contributor.authorGoggi, JL
dc.contributor.authorScerri, T
dc.contributor.authorWilson, GR
dc.contributor.authorLow, CGM
dc.contributor.authorWong, ASW
dc.contributor.authorGrussu, D
dc.contributor.authorStegmann, APA
dc.contributor.authorvan Geel, M
dc.contributor.authorJanssen, R
dc.contributor.authorAmor, DJ
dc.contributor.authorBahlo, M
dc.contributor.authorDunn, NR
dc.contributor.authorCarney, TJ
dc.contributor.authorLockhart, PJ
dc.contributor.authorCoull, BJ
dc.contributor.authorvan Steensel, MAM
dc.date.accessioned2020-12-17T03:49:44Z
dc.date.available2020-12-17T03:49:44Z
dc.date.issued2018-08-15
dc.identifierpii: 4993964
dc.identifier.citationde Vos, I. J. H. M., Tao, E. Y., Ong, S. L. M., Goggi, J. L., Scerri, T., Wilson, G. R., Low, C. G. M., Wong, A. S. W., Grussu, D., Stegmann, A. P. A., van Geel, M., Janssen, R., Amor, D. J., Bahlo, M., Dunn, N. R., Carney, T. J., Lockhart, P. J., Coull, B. J. & 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), pp.2775-2788. https://doi.org/10.1093/hmg/ddy168.
dc.identifier.issn0964-6906
dc.identifier.urihttp://hdl.handle.net/11343/255049
dc.description.abstractWinchester 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.
dc.languageEnglish
dc.publisherOXFORD UNIV PRESS
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleFunctional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype
dc.typeJournal Article
dc.identifier.doi10.1093/hmg/ddy168
melbourne.affiliation.departmentMedical Biology (W.E.H.I.)
melbourne.affiliation.departmentPaediatrics (RCH)
melbourne.affiliation.facultyMedicine, Dentistry & Health Sciences
melbourne.source.titleHuman Molecular Genetics
melbourne.source.volume27
melbourne.source.issue16
melbourne.source.pages2775-2788
melbourne.identifier.nhmrcAPP1032364
dc.rights.licenseCC BY
melbourne.elementsid1328696
melbourne.contributor.authorAmor, David
melbourne.contributor.authorBahlo, Melanie
melbourne.contributor.authorLockhart, Paul
melbourne.contributor.authorScerri, Thomas
melbourne.contributor.authorWilson, Gabrielle
dc.identifier.eissn1460-2083
melbourne.identifier.fundernameidNHMRC, APP1032364
melbourne.accessrightsOpen Access


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