MMP14 – Winchester syndrome

Winchester syndrome (WS) is an extremely rare autosomal recessive skeletal dysplasia characterized by progressive joint destruction, osteolysis, and kyphosis. Affected individuals present with early-onset arthropathy and severe bone resorption leading to functional impairment. Membrane-type 1 matrix metalloproteinase (MMP14) is essential for collagen remodeling, and pathogenic variants that impair its catalytic activity underlie WS. The scarcity of cases has limited large-scale pedigree analysis, but multiple in vitro and in vivo model systems have clarified the mechanistic basis of MMP14-related WS. Integrating genetic and experimental findings supports the durability of this gene-disease association.

Biallelic missense variants in MMP14 have been identified in at least 2 probands with WS ([PMID:29741626]). These patients exhibit autosomal recessive inheritance with no additional segregating relatives reported. The key hypomorphic allele p.Arg111His retains partial collagenolytic activity but yields a mitigated WS phenotype ([PMID:29741626]). No loss-of-function, splice, or recurrent founder variants have yet been described. The limited number of distinct variants and affected families currently constrains the genetic spectrum to collagenase-impairing missense changes.

Functional analyses demonstrate that p.Arg111His does not disrupt MMP14 membrane localization but reduces proteolytic activity essential for extracellular matrix turnover ([PMID:29741626]). MT1-MMP–deficient mice display progressive postnatal growth failure, skeletal dysplasia, and connective tissue defects consistent with collagenase loss ([PMID:15137053]). A zebrafish mmp14a/b knockout recapitulates key features of WS—craniofacial malformations, kyphosis, short stature, and reduced bone density due to defective collagen remodeling ([PMID:29741626]). These concordant models confirm the causative role of impaired MMP14 catalytic function.

Mechanistically, haploinsufficiency of MT1-MMP collagenase activity emerges as the primary pathogenic driver. Degree of residual proteolysis correlates with clinical severity, as hypomorphic mutations produce milder presentations than null alleles. MMP14 cooperates with SH3PXD2B and MMP2 in a defective collagen-remodeling spectrum, reinforcing a unified pathophysiology among osteolytic syndromes ([PMID:31218820]). No studies to date have refuted or significantly weakened MMP14’s central role in WS.

Overall, the genetic and experimental evidence support a Moderate clinical validity classification for MMP14 in autosomal recessive WS. Although proband numbers are limited, strong functional concordance across cellular assays, rodent models, and zebrafish establishes causality. Additional cases, segregation data, and variant characterization will further solidify this association. To date, no alternative gene associations have demonstrated comparable evidence for WS, underscoring the specificity of MMP14.

Key take-home: Biallelic missense alleles impairing MT1-MMP catalytic activity cause Winchester syndrome; the extent of enzymatic retention is the prime determinant of disease severity, guiding both diagnostic interpretation and therapeutic targeting.

References

• Human molecular genetics • 2018 • Functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype. [PMID:29741626]
• American journal of medical genetics. Part A • 2019 • Multicentric osteolytic syndromes represent a phenotypic spectrum defined by defective collagen remodeling. [PMID:31218820]
• Journal of cellular physiology • 2004 • MT1-MMP: a tethered collagenase. [PMID:15137053]

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