Human Molecular Genetics Advance Access originally published online on October 13, 2005
Human Molecular Genetics 2005 14(23):3579-3586; doi:10.1093/hmg/ddi385
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Sorsby's fundus dystrophy mutations impair turnover of TIMP-3 by retinal pigment epithelial cells
1Academic Unit of Pathology, Division of Genomic Medicine, University of Sheffield, Sheffield S10 1EW, UK, 2Department of Gerontology and Department of Rheumatology, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, UK and 3Academic Surgical Oncology Unit, Division of Clinical Sciences, University of Sheffield, Sheffield S10 2JF, UK
* To whom correspondence should be addressed at: Academic Unit of Pathology, Division of Genomic Medicine, University of Sheffield, School of Medicine and Biological Sciences, Beech Hill Road, Sheffield S10 2RX, UK. Tel: +44 1142712547; Fax: +44 1142711711; Email: m.barker{at}shef.ac.uk
Received August 23, 2005; Accepted October 6, 2005
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.
This article is dedicated to our colleague Kevin Langton, who died suddenly on 19th December 2004. We all miss his intellect, practical skills and sense of humor.
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  M. A Majid, V. A Smith, A. C Newby, and A. D Dick Matrix bound SFD mutant TIMP-3 is more stable than wild type TIMP-3 Br. J. Ophthalmol., August 1, 2007; 91(8): 1073 - 1076. [Abstract] [Full Text] [PDF]
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