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

TY - JOUR

T1 - Functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype

AU - de Vos, Ivo J. H. M.

AU - Tao, Evelyn Yaqiong

AU - Ong, Sheena Li Ming

AU - Goggi, Julian L.

AU - Scerri, Thomas

AU - Wilson, Gabrielle R.

AU - Low, Chernis Guai Mun

AU - Wong, Arnette Shi Wei

AU - Grussu, Dominic

AU - Stegmann, Alexander P. A.

AU - van Geel, Michel

AU - Janssen, Renske

AU - Amor, David J.

AU - Bahlo, Melanie

AU - Dunn, Norris R.

AU - Carney, Thomas J.

AU - Lockhart, Paul J.

AU - Coull, Barry

AU - van Steensel, Maurice

N1 - Supported by the Skin Research Institute of Singapore [to M.v.S. and E.Y.T], the Biomedical Research Council Singapore [to M.v.S.], the Agency for Science, Technology and Research [A*STAR Research Attachment Programme to I.d.V.], the Wellcome Trust [DGEM to M.v.S. and B.J.C.], Tenovus Scotland [T15/22 and T15/62 to M.v.S. and B.J.C.], the Victorian Government’s Operational Infrastructure Support Program, and the Australian Government [NHMRC Senior Research Fellowship 110297 and NHMRC Program Grant 1054618 to M.B., NHMRC Career Development Fellowship GNT1032364 to P.J.L.].

PY - 2018/8/15

Y1 - 2018/8/15

N2 - 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.

AB - 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.

U2 - 10.1093/hmg/ddy168

DO - 10.1093/hmg/ddy168

M3 - Article

C2 - 29741626

SN - 0964-6906

VL - 27

SP - 2775

EP - 2788

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 16

M1 - ddy168

ER -