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Human Molecular Genetics Advance Access published online on October 13, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi385
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received August 23, 2005
Revised October 6, 2005
Accepted October 6, 2005

Article

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

Kevin P. Langton 1, Norman McKie 2, Brenda M. Smith 1, Nicola J. Brown 3, and Michael D. Barker 4*

1 Academic Unit of Pathology, Division of Genomic Medicine, University of Sheffield, Sheffield, S10 1EW, UK
2 Departments of Gerontology & Rheumatology, University of Newcastle upon Tyne, Newcastle upon Tyne, NE2 4HH, UK
3 Academic Surgical Oncology Unit, Division of Clinical Sciences, University of Sheffield, Sheffield, S10 2JF, UK
4 Academic Unit of Pathology, Division of Genomic Medicine, University of Sheffield, Sheffield, S10 1EW, UK; Academic Unit of Pathology, Division of Genomic Medicine, University of Sheffield, School of Medicine & Biological Sciences, Beech Hill Road, Sheffield, S10 2RX, UK

* To whom correspondence should be addressed.
Michael D. Barker, E-mail: M.Barker{at}shef.ac.uk


  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.


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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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