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Hum Mol Genet. 2018 Aug 15;27(16):2775-2788. doi: 10.1093/hmg/ddy168.

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

Author information

1
Institute of Medical Biology (IMB), Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore.
2
Department of Dermatology, Maastricht University Medical Center+, Maastricht 6202 AZ, The Netherlands.
3
School for Oncology and Developmental Biology (GROW), Maastricht University Medical Center+, Maastricht 6200 MD, The Netherlands.
4
Singapore Bioimaging Consortium (SBIC), Agency for Science, Technology and Research (A*STAR), Singapore 138667, Singapore.
5
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore 117593, Singapore.
6
Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.
7
Department of Medical Biology, University of Melbourne, Parkville 3052, Australia.
8
Bruce Lefroy Centre for Genetic Health Research, Murdoch Children's Research Institute, Parkville 3052, Australia.
9
Department of Paediatrics, The University of Melbourne, Parkville 3052, Australia.
10
Division of Cancer Research, School of Medicine, University of Dundee, Dundee DD1 9SY, UK.
11
Department of Clinical Genetics, Maastricht University Medical Center+, Maastricht 6229 HX, The Netherlands.
12
Lee Kong Chian School of Medicine, Nanyang Technological University (NTU), Singapore 636921, Singapore.
13
Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore 138673, Singapore.

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.

PMID:
29741626
PMCID:
PMC6077784
DOI:
10.1093/hmg/ddy168
[Indexed for MEDLINE]
Free PMC Article

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