Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease winchester syndrome

Brad R. Evans, Rebecca A. Mosig, Mollie Lobl, Chiara R. Martignetti, Catalina Camacho, Valerie Grum-Tokars, Marc J. Glucksman, John A. Martignetti*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

The "vanishing bone" syndromes represent a group of rare skeletal disorders characterized by osteolysis and joint destruction, which can mimic severe rheumatoid arthritis. Winchester syndrome was one of the first recognized autosomal-recessive, multicentric forms of the disorder. It was originally described nearly 50 years ago in two sisters with a severe crippling osteolysis. Using cultured fibroblasts from the proband, we have now identified homozygous mutations in membrane type-1 metalloproteinase (MT1-MMP or MMP14). We demonstrate that the resulting hydrophobic-region signal-peptide substitution (p.Thr17Arg) decreases MT1-MMP membrane localization with consequent impairment of pro-MMP2 activation, and we propose a structure-based mechanism for this effect.

Original languageEnglish (US)
Pages (from-to)572-576
Number of pages5
JournalAmerican journal of human genetics
Volume91
Issue number3
DOIs
StatePublished - Sep 7 2012

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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