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Sorsby's fundus dystrophy mutations impair turnover of TIMP-3 by retinal pigment epithelial cells

Lookup NU author(s): Dr Norman Balfour-McKie


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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. © The Author 2005. Published by Oxford University Press. All rights reserved.

Publication metadata

Author(s): Langton KP, McKie N, Smith BM, Brown NJ, Barker MD

Publication type: Article

Publication status: Published

Journal: Human Molecular Genetics

Year: 2005

Volume: 14

Issue: 23

Pages: 3579-3586

ISSN (print): 0964-6906

ISSN (electronic): 1460-2083

Publisher: Oxford University Press


DOI: 10.1093/hmg/ddi385

PubMed id: 16223891


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