title: 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.affiliation: Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: Brad R
authors.initials: BR
authors.lastname: Evans
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Mosig
authors.forename: Mollie
authors.initials: M
authors.lastname: Lobl
authors.forename: Chiara R
authors.initials: CR
authors.lastname: Martignetti
authors.forename: Catalina
authors.initials: C
authors.lastname: Camacho
authors.forename: Valerie
authors.initials: V
authors.lastname: Grum-Tokars
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Glucksman
authors.forename: John A
authors.initials: JA
authors.lastname: Martignetti
mesh_terms: D000015:Abnormalities, Multiple / Q000000981:diagnostic imaging / Q000235:genetics*; D000595:Amino Acid Sequence; D001168:Arthritis / Q000235:genetics*; D003286:Contracture / Q000000981:diagnostic imaging / Q000235:genetics*; D003318:Corneal Opacity / Q000000981:diagnostic imaging / Q000235:genetics*; D005260:Female; D006130:Growth Disorders / Q000000981:diagnostic imaging / Q000235:genetics*; D031845:Hajdu-Cheney Syndrome / Q000235:genetics*; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000235:genetics*; D008958:Models, Molecular; D009154:Mutation; D010014:Osteolysis / Q000000981:diagnostic imaging / Q000235:genetics*; D010024:Osteoporosis / Q000000981:diagnostic imaging / Q000235:genetics*; D011859:Radiography
chemical_list: C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14