Abstract
The hereditary macular dystrophies are progressive degenerations of the central retina and contribute significantly to irreversible visual loss in developed countries. Among these disorders, Sorsby's fundus dystrophy (SFD), an autosomal dominant condition, provides an excellent mendelian model for the study of the genetically complex age-related macular degeneration (AMD), the most common maculopathy in the elderly. Recently, we mapped the SFD locus to 22q13–qter. This same region contains the gene for tissue inhibitor of metalloproteinases-3 (TIMP3), which is known to play a pivotal role in extracellular matrix remodeling. We have now identified point mutations in the TIMP3 gene in affected members of two SFD pedigrees. These mutations are predicted to disrupt the tertiary structure and thus the functional properties of the mature protein.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Klein, R., Klein, B.E. & Linton, K.L.P. Prevalence of age-related maculopathy: The Beaver Dam Eye Study. Ophthalmology 99, 933–943 (1992).
Sorsby, A., Mason, M.E.J. & Gardener, N. A fundus dystrophy with unusual features. Br. J. Ophthalmol. 33, 67–97 (1949).
Capon, M.R.C., Marshall, J., Krafft, J.I., Alexander, R.A., Hiscott, P.S. & Bird, A.C. Sorsby's fundus dystrophy — A light and electron microscopic study. Ophthalmol. 96, 1769–1777 (1989).
Bressler, N.M., Bressler, S.B. & Fine, S.L. Age-related macular degeneration. Survey Ophthalmology 32, 375–413 (1988).
Lin, W.-L Immunogold localization of extracellular matrix molecules in Bruch's membrane of the rat. Curr. Eye Res. 8, 1171–1178 (1989).
Matrisian, L.M. Metalloproteinases and their inhibitors in matrix remodeling. Trends Genet. 6, 121–125 (1990).
Docherty, A.J.P., O'Connell, J., Crabbe, T., Angal, S. & Murphy, G. The matrix metalloproteinases and their natural inhibitors: prospects for treating degenerative tissue diseases. Trends Biotech. 10, 200–207 (1992).
Pelletier, J.P., Mineau, F., Faure, M.P. & Martel-Pelletier, J. Imbalance between the mechanisms of activation and inhibition of metalloproteinases in the early lesions of experimental osteoarthritis. Arthritis Rheum. 33, 1466–1476 (1990).
D'Armiento, J., Dalal, S.S., Okada, Y., Berg, R.A. & Chada, K. Collagenase expression in the lungs of transgenic mice causes pulmonary emphysema. Cell 71, 955–961 (1992).
Henney, A.M. et al. Localization of stromelysin gene expression in atherosclerotic plaques by in situ hybridization. Proc. natn. Acad. Sci. U.S.A. 88, 8154–8158 (1991).
Milani, S. et al. Differential expression of matrix-metalloproteinase-1 and -2 genes in normal and fibrotic human liver. Am. J. Pathol. 144, 528–537 (1994).
Khokha, R. & Denhardt, D.T. Matrix metalloproteinases and tissue inhibitor of metalloproteinases: a review of their role in tumorigenesis and tissue invasion. Invasion Metastasis 9, 391–405 (1989).
Apte, S.S., Mattei, M.G. & Olsen, B.R. Cloning of the cDNA encoding human tissue inhibitor of metalloproteinases-3 (TIMP-3) and mapping of the TIMP-3 gene to chromosome 22. Genomics 19, 86–90 (1994).
Silbiger, S.M., Jacobsen, V.L., Cupples, R.L. & Koski, R.A. Cloning of cDNAs encoding human TIMP-3, a novel member of the tissue inhibitor of metalloproteinase family. Gene 141, 293–297 (1994).
Weber, B.H.F., Vogt, G., Wolz, W., Ives, E.J. & Ewing, C.C. Sorsby's fundus dystrophy is genetically linked to chromosome 22q13–qter. Nature Genet. 7, 158–161 (1994).
Hamilton, W.K., Ewing, C.C., Ives, E.J. & Carruthers, J.D. Sorsby's fundus dystrophy. Ophthalmology 96, 1755–1762 (1989).
Wu, G., Pruett, R.C., Baldinger, J. & Hirose, T. Hereditary hemorrhagic macular dystrophy. Am. J. Ophthalmol. 111, 294–301 (1991).
Orita, V., Suzuki, Y., Sekiya, T. & Hayashi, K. Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction. Genomics 5, 874–879 (1989).
Leco, K.J. et al. Tissue inhibitor of metalloproteinases-3 (TIMP-3) is an extracellular matrix-associated protein with a distinctive pattern of expression in mouse cells and tissues. J. biol. Chem. 269, 9352–9360 (1994).
Gasson, J.C. et al. Molecular characterization and expression of the gene encoding human erythroid-potentiating activity. Nature 315, 768–771 (1985).
Boone, T.C., Johnson, M.J., De Clerck, Y.A. & Langley, K.E. cDNA cloning and expression of a metalloproteinase inhibitor related to tissue inhibitor of metalloproteinases. Proc. natn. Acad. Sci. U.S.A. 87, 2800–2804 (1990).
Williamson, R.A. et al. Disulphide bond assignment in human tissue inhibitor of metalloproteinases (TIMP). Biochem. J. 268, 267–274 (1990).
Bertaux, B., Homebeck, W., Eisen, A.Z. & Dubertret, L. Growth stimulation of human keratinocytes by tissue inhibitor of metalloproteinases. J. invest. Dermatol. 97, 679–685 (1991).
Yang, T.T. & Hawkes, S.P. Role of the 21-kDa protein TIMP-3 in oncogenic transformation of cultured chicken embryo fibroblasts. Proc. natn. Acad. Sci. U.S.A. 89, 10676–10680 (1992).
Moses, M.A., Sudhalter, J. & Langer, R. Identification of an inhibitor of neovascularization from cartilage. Science 248, 1408–1410 (1990).
Pauleikhoff, D., Chen, J.C., Chisholm, I.H. & Bird, A.C. Choroidal perfusion abnormality with age-related Bruch's membrane change. Am. J. Ophthalmol. 109, 211–217 (1990).
Duvall, J. et al. Extensive subretinal pigment epithelial deposits in two brothers suffering from dominant retinitis pigmentosa. A histopathological study. Graefes Arch. Clin. Exp. Ophthalmol. 224, 299–309 (1986).
Meyer, K.T., Heckenlively, J.R., Spitznas, M. & Foos, R.Y. Dominant retinitis pigmentosa. A clinicopathological correlation. Ophthalmology 89, 1414–1424 (1982).
Santos-Anderson, R.M., Tso, M.O.M. & Fishman, G.A. A histopathologic study of retinitis pigmentosa. Ophthalmic. Paediatr. Genet. 1, 151–168 (1982).
Derry, J.M. & Barnard, P.J. Physical linkage of the A-raf-1, properdin, synapsin I, and TIMP genes on the human and mouse X chromosomes. Genomics 12, 632–638 (1992).
De Clerck, Y., Szpirer, C., Aly, M.S., Cassiman, J.J., Eeckhout, Y. & Rousseau, G. The gene for tissue inhibitor of metalloproteinases-2 is localized on human chromosome arm 17q25. Genomics 14, 782–784 (1992).
Sanger, F., Nicklen, S. & Coulson, A.R. DNA sequencing with chain-terminating inhibitors. Proc. natn. Acad. Sci. U.S.A. 74, 5463–5467 (1977).
Pavloff, N., Staskus, P.W., Kishnani, N.S. & Hawkes, S.P. A new inhibitor of metalloproteinases from chicken: chTIMP-3. A third member of the TIMP family. J. biol. Chem. 267, 17321–17326 (1992).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Weber, B., Vogt, G., Pruett, R. et al. Mutations in the tissue inhibitor of metalloproteinases-3 (TIMP3) in patients with Sorsby's fundus dystrophy. Nat Genet 8, 352–356 (1994). https://doi.org/10.1038/ng1294-352
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ng1294-352
This article is cited by
-
Oxidative stress differentially impacts apical and basolateral secretion of angiogenic factors from human iPSC-derived retinal pigment epithelium cells
Scientific Reports (2022)
-
Treatment of Sorsby fundus dystrophy with anti-tumor necrosis factor-alpha medication
Eye (2022)
-
Clinically-identified C-terminal mutations in fibulin-3 are prone to misfolding and destabilization
Scientific Reports (2021)
-
Proline metabolism and transport in retinal health and disease
Amino Acids (2021)