title: Sorsby's fundus dystrophy mutations impair turnover of TIMP-3 by retinal pigment epithelial cells.
abstract: Sorsby's fundus dystrophy (SFD) is an autosomal dominant degenerative disease of the retina, caused by mutations in exon 5 of the gene for tissue inhibitor of metalloproteinases-3 (TIMP-3). The mechanism by which these mutations give rise to the disease phenotype is unknown. In an attempt to identify common properties of these molecules that might underlie the disease phenotype, a range of SFD mutants were expressed from human retinal pigment epithelial (RPE) cells. This showed that resistance to turnover, resulting from intermolecular disulfide bond formation, was a common property of all the SFD mutants examined, providing a possible explanation for the increased deposition of the protein observed in eyes from SFD patients. In contrast, SFD mutants varied in their ability to inhibit cell-surface activation of matrix metalloproteinase-2 (MMP-2), a potent mediator of angiogenesis, ranging from being fully active to totally inactive. These data show that increased deposition of active TIMP-3, rather than dysregulation of metalloproteinase inhibition, is likely to be the primary, initiating event in SFD.
authors.affiliation: Academic Unit of Pathology, Division of Genomic Medicine, University of Sheffield, Sheffield S10 1EW, UK.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Langton
authors.forename: Norman
authors.initials: N
authors.lastname: McKie
authors.forename: Brenda M
authors.initials: BM
authors.lastname: Smith
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Brown
authors.forename: Michael D
authors.initials: MD
authors.lastname: Barker
mesh_terms: D002478:Cells, Cultured; D005654:Fundus Oculi; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D009154:Mutation; D010857:Pigment Epithelium of Eye / Q000201:enzymology / Q000378:metabolism*; D012162:Retinal Degeneration / Q000235:genetics / Q000378:metabolism*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics* / Q000378:metabolism*
chemical_list: D019717:Tissue Inhibitor of Metalloproteinase-3; D020778:Matrix Metalloproteinase 2