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

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.

What does acne genetics teach us about disease pathogenesis?

“…[78][79][80] We have previously reported that it can cause severe acne with hypertrophic scarring and thickened skin. 81 Mutations in MMP14 have been associated with WS via one mutation that decreases the membrane localization and another that disrupts the catalytic activity, resulting in impaired pro-MMP2 activation. 81,82 WS is part of a continuous clinical spectrum together with multicentric osteolysis, nodulosis and arthropathy (MONA) syndrome, Torg syndrome and nodulosisarthropathy-osteolysis (NAO) syndrome (MIM 259600).…”

“…81 Mutations in MMP14 have been associated with WS via one mutation that decreases the membrane localization and another that disrupts the catalytic activity, resulting in impaired pro-MMP2 activation. 81,82 WS is part of a continuous clinical spectrum together with multicentric osteolysis, nodulosis and arthropathy (MONA) syndrome, Torg syndrome and nodulosisarthropathy-osteolysis (NAO) syndrome (MIM 259600). 81 Based on the identification of MMP2 gene mutations, MONA, Torg and NAO syndromes were originally thought to be distinct from WS, but they are now seen as allelic disorders due to overlapping mechanisms of action.…”

“…81,82 WS is part of a continuous clinical spectrum together with multicentric osteolysis, nodulosis and arthropathy (MONA) syndrome, Torg syndrome and nodulosisarthropathy-osteolysis (NAO) syndrome (MIM 259600). 81 Based on the identification of MMP2 gene mutations, MONA, Torg and NAO syndromes were originally thought to be distinct from WS, but they are now seen as allelic disorders due to overlapping mechanisms of action. 79,[83][84][85] Disease-causing MMP14 mutations result in a lack of activated MMP2, 81,82 explaining the phenotypic continuity and justifying their grouping into one spectrum.…”

“…81 Based on the identification of MMP2 gene mutations, MONA, Torg and NAO syndromes were originally thought to be distinct from WS, but they are now seen as allelic disorders due to overlapping mechanisms of action. 79,[83][84][85] Disease-causing MMP14 mutations result in a lack of activated MMP2, 81,82 explaining the phenotypic continuity and justifying their grouping into one spectrum. Interestingly, genetic variants in MMP2 have also been reported to be associated with acne vulgaris.…”

Multicentric osteolytic syndromes represent a phenotypic spectrum defined by defective collagen remodeling

“…Rather, we found a novel homozygous missense MMP14 mutation in these patients (Wilson et al, ). We recently reported that it mostly likely represents a hypomorphic allele (De Vos et al, ).…”