PUBLICATION

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

Authors
de 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.
ID
ZDB-PUB-180510-9
Date
2018
Source
Human molecular genetics   27(16): 2775-2788 (Journal)
Registered Authors
Carney, Tom
Keywords
none
MeSH Terms
  • Zebrafish
  • Mice
  • Gene Knockout Techniques
  • Humans
  • Craniofacial Abnormalities/genetics*
  • Craniofacial Abnormalities/physiopathology
  • Abnormalities, Multiple/genetics*
  • Abnormalities, Multiple/physiopathology
  • Matrix Metalloproteinase 14/genetics*
  • Phenotype
  • Catalytic Domain/genetics
  • Alleles
  • Contracture/genetics*
  • Contracture/physiopathology
  • Corneal Opacity/genetics*
  • Corneal Opacity/physiopathology
  • Osteoporosis/genetics*
  • Osteoporosis/physiopathology
  • Growth Disorders/genetics*
  • Growth Disorders/physiopathology
  • Osteolysis/genetics*
  • Osteolysis/physiopathology
  • Animals
(all 23)
PubMed
29741626 Full text @ Hum. Mol. Genet.
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 due to defective collagen remodeling. Notably, the zebrafish model will be a valuable tool for developing novel therapeutic approaches to a devastating bone disorder.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
No data available
Fish
Fish
AB
mmp14azf2194/zf2194 (AB)
mmp14azf2194/zf2194; mmp14bzf2195/zf2195 (AB)
mmp14bzf2195/zf2195 (AB)
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Antibodies
No data available
Orthology
No data available
Engineered Foreign Genes
No data available
Mapping
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Citation
de 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):2775-2788.