The molecular pathology of Sorsby fundus dystrophy: the role of the extracellular matrix in the neurodegeneration of the human retina
Project management at the University of Würzburg:
The extracellular matrix (ECM) mediates important cellular functions such as cell adhesion, cell-cell communication, cell-matrix interactions as well as intercellular transport. Remodeling of the ECM is an essential component of normal development and consists of a continously occuring synthesis and degradation of ECM molecules. These processes involve a family of tightly regulated matrix metalloproteinases (MMPs) as well as other proteolytic enzyme groups such as the serine or cysteine proteinases. To ensure ECM integrity, the control of MMP activity is complex and occurs at the level of transcription and enzyme activation/inhibition. Disturbances in the regulation of the metalloproteinases, in particular between the MMPs and their natural inhibitors, the tissue inhibitors of metalloproteinases (TIMPs) may lead to degenerative and proliferative diseases such as rheumatoid arthritis, pulmonary emphysema, artherosclerosis, and liver fibrosis but are also thought to enable malignant cells to penetrate basement membranes and to metastasize. To facilitate in vivo investigations of mutant TIMP3 we have generated knock-in mice carrying a Ser156Cys mutation in the orthologous murine Timp3 gene via homologous recombination in embryonic stem cells. This as well as other known mutations in human introduce potentially unpaired cysteine residues in the C-terminus of the protein and result in the formation of higher molecular weight protein complexes of as yet unknown composition and functional consequence for SFD pathology. In contrast to the human phenotype, adult heterozygous Ser156Cys mice develop only a mild phenotype. The RPE is primarily affected with the most prominent abnormalities occurring in the organization of the basal microvilli. No other histological signs of pathology are evident in other retinal tissues and electrodiagnostic recordings suggest that retinal function remains normal throughout life in both heterozygous and homozygous Ser156Cys mice. The biochemical characteristics of the mutant protein, however, are similar in human and knock-in mice, suggesting common molecular pathways in the two species. Investigation into this mouse model will elucidate the functional role of the extracellular matrix in RPE physiology and may shed light onto the molecular pathology in Sorsby fundus dystrophy.
Sorsby fundus dystrophy
from 07.2000 to 06.2003
DFG ( SFB581 ) ,Granting date: 23.06.2000
- Weber BHF, Vogt G, Pruett RC, Stöhr H, Felbor U.
(1994). Mutations in the tissue inhibitor of metalloproteinases-3 (TIMP-3) in patients with Sorsby's fundus dystrophy. Nature Genet 8, 352-356, (scientific article)
- Felbor U, Stöhr H, Amann T, Schönherr U, Weber BHF.
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- Stöhr H, Roomp K, Felbor U, Weber BHF.
(1995). Genomic organization of the human tissue inhibitor of metalloproteinases-3 (TIMP3). Genome Res 5, 483-487, (scientific article)
- Felbor U, Schilling H, Weber BHF.
(1996). Adult vitelliform macular dystrophy is frequently associated with mutations in the peripherin/RDS gene. Hum Mutat 10, 301-309, (scientific article)
- Felbor U, Suvanto EA, Forsius HR, Eriksson AW, Weber BHF.
(1997). Autosomal recessive Sorsby fundus dystrophy revisited: Molecular evidence for dominant inheritance. Am J Hum Genet 60, 57-62, (scientific article)
- Felbor U, Doepner D, Schneider U, Zrenner E, Weber BHF.
(1997). Evaluation of the gene encoding the tissue inhibitor of metalloproteinases-3 (TIMP3) in various macular dystrophies. Invest Ophthalmol Vis Sci 38, 1054-1059, (scientific article)
- Felbor U, Benkwitz C, Klein ML, Greenberg J, Gregory CY, Weber BHF.
(1997). Sorsby's fundus dystrophy: Reevaluation of variable expressivity in patients carrying a TIMP3 founder mutation. Arch Ophthalmol 115, 1569-1571, (scientific article)
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(1998). Genomic organization and chromosomal localization of a novel interphotoreceptor matrix proteoglycan-1 (IMPG1): A candidate for 6q-linked retinopathies. Cytogenet Cell Genet 81, 12-17, (scientific article)
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(2002). A mouse model for Sorsby fundus dystrophy displays early features of age-related changes in Bruch?s membrane and the basal microvilli of the RPE. Invest Ophthalmol Vis Sci 43: 2732-2740, (scientific article)