A novel Ser156Cys mutation in the tissue inhibitor of metalloproteinases-3 (TIMP3) in Sorsby's fundus dystrophy with unusual clinical features

Felbor, Ute; Stöhr, Heidl; Amann, Thomas; Schönherr, Ulrich; Weber, Bernhard H. F.

doi:10.1093/hmg/4.12.2415

Cited by 60 publications

(45 citation statements)

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“…22 Mutations in TIMP3 were implicated in Sorsby's fundus dystrophy (SFD), an autosomal dominant disorder featuring accumulation of macular drusen and progression to CNV and retinal degeneration. [23][24][25][26] In SFD as well as in the TIMP3-independent dystrophic disease retinitis pigmentosa, accumulation of TIMP3 was observed by immunohistochemistry, highlighting the importance of ECM turnover in the pathologic state. 27 At the same time, SFD is known to be caused by missense mutations within TIMP3 exons, which are likely to alter ECM integrity qualitatively by either changing TIMP3 binding specificity or affinity for its substrates.…”

Section: Discussionmentioning

confidence: 97%

Influence of TIMP3/SYN3 polymorphisms on the phenotypic presentation of age-related macular degeneration

et al. 2013

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Age-related macular degeneration (AMD) is a leading cause of irreversible central visual loss in the elderly. A recent genomewide association studies (GWAS) reported that rs9621532 near the tissue inhibitor of metalloproteinase 3 (TIMP3)/synapsin III (SYN3) region of 22q12.3 is associated with AMD. In this study, we characterize its phenotypic influence on AMD using three independent study cohorts: case-control studies from the National Eye Institute Clinical Center (NEI, n ¼ 397) and the AgeRelated Eye Disease Study (n ¼ 523) as well as a nested case-control study from Blue Mountains Eye Study (BMES, n ¼ 852).Comparisons between cases and controls show no association between rs9621532 and AMD in the three sample sets. However, stratifying NEI cases uncovers a moderate protective role of rs9621532 in neovascular AMD (nAMD) and the association adhered to a dominant model (odds ratios ¼ 0.32; 95% CI: 0.11-0.89; P ¼ 0.02). The BMES data followed the same pattern of association with nAMD as that seen in the NEI sample but did not reach statistical significance. Polychotomous logistic regression showed a trend that rs9621532 correlates with less severe disease, for example, with the majority of carriers having intermediate AMD rather than nAMD/geographic atrophy AMD. Functionally, rs9621532 influences TIMP3 mRNA expression in cultured primary human fetal retinal pigment epithelium (hfRPE) cells. In hfRPE donors carrying the protective rs9625132 allele, we measured a reduction in TIMP3 mRNA by quantitative RT-PCR. Our data suggest that rs9621532 carriers have a lower risk of developing nAMD, potentially because of decreased transcription of TIMP3.

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Section: Discussionmentioning

confidence: 97%

Influence of TIMP3/SYN3 polymorphisms on the phenotypic presentation of age-related macular degeneration

et al. 2013

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“…TIMP-3 protein is produced constitutively by the retina pigment epithelium (RPE) and choroidal endothelial cells (9,10) in the eye and is a component of the normal Bruch membrane (11). Sorsby fundus dystrophy (SFD) (12), a dominantly inherited, degenerative disease of the macula, is caused by specific mutations in the TIMP-3 gene (13)(14)(15)(16)(17)(18)(19)(20), most of which introduce an unpaired cysteine at the C terminus of the protein. SFD is of considerable interest as it is the only genetic disorder in which choroidal neovascularization occurs in the majority of affected patients (21)(22)(23).…”

Section: Tissue Inhibitor Of Metalloproteinases-3 (Timp-3)mentioning

confidence: 99%

S156C Mutation in Tissue Inhibitor of Metalloproteinases-3 Induces Increased Angiogenesis

Dai

Luthert

et al. 2009

Journal of Biological Chemistry

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Tissue Inhibitor of metalloproteinases-3 (TIMP-3) is a potent matrix-bound angiogenesis inhibitor. Mutations in TIMP-3 cause Sorsby Fundus Dystrophy, a dominant inherited, early onset macular degenerative disease, with choroidal neovascularization causing a loss of vision in the majority of patients. Here we report that expression of S156C TIMP-3 mutation in endothelial cells results in an abnormal localization of the protein, increased glycosylation, decreased matrix metalloproteinase inhibitory activity, and increased vascular endothelial growth factor (VEGF) binding with a consequent increase in VEGF-dependent migration and tube formation. These enhanced signaling events appear to be mediated as a consequence of a post-transcriptionally regulated increase in the expression of membrane-associated VEGFR-2 in endothelial cells of Timp-3 156/156 mutant mice as well as in human Sorsby fundus dystrophy eyes. Understanding the mechanism(s) by which mutant TIMP-3 can induce abnormal neovascularization provides important insight into the pathophysiology of a number of diseases with increased angiogenesis. Tissue inhibitor of metalloproteinases-3 (TIMP-3)2 is a member of the TIMP family of proteins and is an endogenous inhibitor of matrix metalloproteinases (MMPs), a disintegrin and metalloproteinase (ADAM), and ADAM with thrombospondin domains (ADAMTS) family of enzymes. TIMP-3 is unique among other members of the TIMP family in that it is tightly bound to the extracellular matrix (ECM). In addition, TIMP-3 is the only TIMP that can inhibit tumor necrosis factor ␣-converting enzyme (TACE/ADAM17) and aggrecanase 1 and 2 (ADAMTS4 and ADAMTS5). Functionally, apart from being a key inhibitor of MMPs (1, 2) and regulating apoptosis in some cells in vitro and in vivo (3-7), TIMP-3 has been demonstrated to be a potent inhibitor of angiogenesis through its ability to block the binding of VEGF to its receptor VEGFR-2 (also known as KDR and FLK-1), affecting subsequent receptor downstream signaling (8). TIMP-3 protein is produced constitutively by the retina pigment epithelium (RPE) and choroidal endothelial cells (9, 10) in the eye and is a component of the normal Bruch membrane (11). Sorsby fundus dystrophy (SFD) (12), a dominantly inherited, degenerative disease of the macula, is caused by specific mutations in the TIMP-3 gene (13-20), most of which introduce an unpaired cysteine at the C terminus of the protein. SFD is of considerable interest as it is the only genetic disorder in which choroidal neovascularization occurs in the majority of affected patients (21-23). SFD-TIMP-3 protein accumulates in deposits in Bruch membrane (24) and shows pro-apoptotic activity (25) and reduced MMP inhibitory activity (10). Whether SFD-TIMP-3 affects VEGFR-2-mediated VEGF signaling specific to angiogenesis is unknown. In this study we have generated endothelial cells (ECs) expressing SFD-related S156C TIMP-3 mutation as a platform and determined how mutant TIMP-3 regulates VEGF signaling via VEGFR-2 during SFD-related angiogenesis. In ad...

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“…TIMP-3 can also inhibit members 4 and 5 of the ADAMTS group, enzymes that are responsible for aggrecan degradation in cartilage (15). TIMP-3 is the only TIMP known to be related to a disease: mutation of certain cysteine residues to serine results in deposition of excessive amounts of TIMP-3 in Bruch's membrane, producing early blindness, a condition known as Sorsby fundus dystrophy (16).…”

Section: Role Of Timpsmentioning

confidence: 99%

That impish TIMP: the tissue inhibitor of metalloproteinases-3

Woessner¹

2001

J. Clin. Invest.

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A novel Ser156Cys mutation in the tissue inhibitor of metalloproteinases-3 (TIMP3) in Sorsby's fundus dystrophy with unusual clinical features

Cited by 60 publications

References 0 publications

Influence of TIMP3/SYN3 polymorphisms on the phenotypic presentation of age-related macular degeneration

Influence of TIMP3/SYN3 polymorphisms on the phenotypic presentation of age-related macular degeneration

S156C Mutation in Tissue Inhibitor of Metalloproteinases-3 Induces Increased Angiogenesis

That impish TIMP: the tissue inhibitor of metalloproteinases-3

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