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

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.

• Authors: Brad R Evans, Rebecca A Mosig, Mollie Lobl, Chiara R Martignetti, Catalina Camacho, Valerie Grum-Tokars, Marc J Glucksman, John A Martignetti
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 91 Issue 3 Pg. 572-6 (Sep 07 2012) ISSN: 1537-6605 [Electronic] United States
• PMID: 22922033 (Publication Type: Journal Article)
• Copyright: Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Chemical References

• MMP14 protein, human
• Matrix Metalloproteinase 14

Topics

• Abnormalities, Multiple (diagnostic imaging, genetics)
• Amino Acid Sequence
• Arthritis (genetics)
• Contracture (diagnostic imaging, genetics)
• Corneal Opacity (diagnostic imaging, genetics)
• Female
• Growth Disorders (diagnostic imaging, genetics)
• Hajdu-Cheney Syndrome (genetics)
• Humans
• Matrix Metalloproteinase 14 (genetics)
• Models, Molecular
• Mutation
• Osteolysis (diagnostic imaging, genetics)
• Osteoporosis (diagnostic imaging, genetics)
• Radiography