Mutations in the tissue inhibitor of metalloproteinases-3 (TIMP3) in patients with Sorsby's fundus dystrophy

Weber, Bernhard H. F.; Vogt, Gudrun; Pruett, Ronald C.; Stöhr, Heidi; Felbor, Ute

doi:10.1038/ng1294-352

Cited by 599 publications

(312 citation statements)

References 31 publications

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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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“…A polymorphism in TIMP-3 was found in patients with Sorsby's fundus dystrophy, a hereditary condition that is associated with early development of CNV (Weber et al, 1994), but evidence thus far does not show that TIMP-3 plays a strong role in AMD. However, a binding partner to TIMP-3, known as fibulin 3 or epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP-1), was found in Malattia Leventinese, a genetic condition associated with a specific appearance of drusen.…”

Section: Extracellular Matrix Proteolysis and Vegf-proteolytic Enzymementioning

confidence: 99%

Vascular endothelial growth factor in eye disease

Penn

Madan

Caldwell

et al. 2008

Progress in Retinal and Eye Research

636

527

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Collectively, angiogenic ocular conditions represent the leading cause of irreversible vision loss in developed countries. In the U.S., for example, retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration are the principal causes of blindness in the infant, working age and elderly populations, respectively. Evidence suggests that vascular endothelial growth factor (VEGF), a 40 kDa dimeric glycoprotein, promotes angiogenesis in each of these conditions, making it a highly significant therapeutic target. However, VEGF is pleiotropic, affecting a broad spectrum of endothelial, neuronal and glial behaviors, and confounding the validity of anti-VEGF strategies, particularly under chronic disease conditions. In fact, among other functions VEGF can influence cell proliferation, cell migration, proteolysis, cell survival and vessel permeability in a wide variety of biological contexts. This article will describe the roles played by VEGF in the pathogenesis of retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration. The potential disadvantages of inhibiting VEGF will be discussed, as will the rationales for targeting other VEGF-related modulators of angiogenesis.

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“…Multiple TIMP gene mutations have been described and have been related to a number of noncardiovascular diseases. Sorsby's fundus dystrophy, a rare dominantly inherited degenerative disease of the retina, has been causally related to mutations in the gene encoding for TIMP3 (Weber et al 1994, John et al 1998. In a further small study of 128 patients, TIMP2 polymorphisms have been associated with chronic obstructive lung disease (Hirano et al 2001).…”

Section: Introductionmentioning

confidence: 99%

Premature coronary artery disease shows no evidence of linkage to loci encoding for tissue inhibitors of matrix metalloproteinases

et al. 2003

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Tissue inhibitors of metalloproteinases (TIMP1, TIMP2, TIMP3) are naturally occurring inhibitors of matrix metalloproteinases (MMPs). It has been proposed that MMPs have a role in weakening the fibrous cap and subsequent plaque rupture. We hypothesized that TIMP polymorphisms could predispose to premature coronary artery disease. As a first step, we examined the relevant loci using a linkage approach. Sibling pairs recruited for the British Heart Foundation (BHF) Family Heart Study with premature coronary artery disease were examined. Two to three microsatellite markers were examined per TIMP gene. These markers were either intragenic or very close to the locus encoding for the gene. Products were analyzed by capillary gel electrophoresis. Single and multipoint linkage analysis based on the likelihood ratio test was performed using SPLINK and Mapmaker/Sibs software; 417 families were genotyped consisting of 385 sibling pairs, 27 trios, and five sets of four siblings. We were unable to detect linkage of premature coronary artery disease to loci encoding for TIMP1-3. Polymorphisms of the tissue inhibitors of MMP genes do not predispose to premature coronary artery disease in an epidemiologically significant way.

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Mutations in the tissue inhibitor of metalloproteinases-3 (TIMP3) in patients with Sorsby's fundus dystrophy

Cited by 599 publications

References 31 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

Vascular endothelial growth factor in eye disease

Premature coronary artery disease shows no evidence of linkage to loci encoding for tissue inhibitors of matrix metalloproteinases

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