A Novel TIMP3 Mutation Associated With Sorsby Fundus Dystrophy

Barbazetto, Irene; Hayashi, Masanori; Klais, Christina M.; Yannuzzi, Lawrence A.; Allikmets, Rando

doi:10.1001/archopht.123.4.542

Cited by 28 publications

(21 citation statements)

References 4 publications

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“…SFD is caused by specific mutations in the tissue inhibitor of metalloproteinases-3 ( TIMP-3 ) gene [30], [31], [32], [33], [34], [35], [36], [37], most of which introduce an unpaired cysteine at the C-terminus of the protein. We have recently reported that S156C mutation in TIMP-3 induces increased angiogenesis [18] and that mice lacking TIMP-3 show increased laser-induced CNV [38].…”

Section: Discussionmentioning

confidence: 99%

Tissue Inhibitor of Metalloproteinases-3 Peptides Inhibit Angiogenesis and Choroidal Neovascularization in Mice

Ebrahem

et al. 2013

PLoS ONE

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Tissue inhibitors of metalloproteinases (TIMPs) while originally characterized as inhibitors of matrix metalloproteinases (MMPs) have recently been shown to have a wide range of functions that are independent of their MMP inhibitory properties. Tissue inhibitor of metalloproteinases-3 (TIMP-3) is a potent inhibitor of VEGF-mediated angiogenesis and neovascularization through its ability to block the binding of VEGF to its receptor VEGFR-2. To identify and characterize the anti-angiogenic domain of TIMP-3, structure function analyses and synthetic peptide studies were performed using VEGF-mediated receptor binding, signaling, migration and proliferation. In addition, the ability of TIMP-3 peptides to inhibit CNV in a mouse model was evaluated. We demonstrate that the anti-angiogenic property resides in the COOH-terminal domain of TIMP-3 protein which can block the binding of VEGF specifically to its receptor VEGFR-2, but not to VEGFR-1 similar to the full-length wild-type protein. Synthetic peptides corresponding to putative loop 6 and tail region of TIMP-3 have anti-angiogenic properties as determined by inhibition of VEGF binding to VEGFR-2, VEGF-induced phosphorylation of VEGFR-2 and downstream signaling pathways as well as endothelial cell proliferation and migration in response to VEGF. In addition, we show that intravitreal administration of TIMP-3 peptide could inhibit the size of laser-induced choroidal neovascularization lesions in mice. Thus, we have identified TIMP-3 peptides to be efficient inhibitors of angiogenesis and have a potential to be used therapeutically in diseases with increased neovascularization.

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Section: Discussionmentioning

confidence: 99%

Tissue Inhibitor of Metalloproteinases-3 Peptides Inhibit Angiogenesis and Choroidal Neovascularization in Mice

Ebrahem

et al. 2013

PLoS ONE

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“…The proband, his mother, and maternal uncle are affected by SFD. 13 Tissue inhibitor of metalloproteinases 3 has been shown to inhibit angiogenesis by blocking binding of vascular endothelial growth factor to vascular endothelial growth factor receptor 2. In addition, his maternal grandmother had bilateral "macular degeneration" and was legally blind by the age of 60 years, and 3 of his 6 maternal aunts, his great grandmother, and 2 great maternal aunts developed visual deterioration by middle age.…”

Section: Discussionmentioning

confidence: 99%

Atypical Sorsby Fundus Dystrophy With a Novel Tyr159cys Timp-3 Mutation

Fung¹,

Stöhr

Weber

et al. 2013

RETINAL Cases &Amp; Brief Reports

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“…7 Before this article, 11 distinct mutations have been described, all occurring at the Exon 5 site of the C-terminal domain of the protein. 2,[7][8][9][10][11][12][13][14][15][16][17] Of these, seven mutations result in unpaired cysteine residues. 7,10-16 Two mutations change the net charge of the protein and may affect nearby cysteine residues.…”

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confidence: 99%

A Novel Mutation at the N-Terminal Domain of the Timp3 Gene in Sorsby Fundus Dystrophy

Schoenberger

2013

Retina

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All previously reported mutations in Sorsby fundus dystrophy occur at Exon 5 in the C-terminal domain. We report 2 patients with novel mutations in Exon 1 of the N-terminal domain. Although the mutation occurs at a different location on the TIMP3 gene, the clinical features are similar to other reported patients with Sorsby fundus dystrophy. This finding assists in understanding the pathogenesis of this disorder.

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A Novel TIMP3 Mutation Associated With Sorsby Fundus Dystrophy

Cited by 28 publications

References 4 publications

Tissue Inhibitor of Metalloproteinases-3 Peptides Inhibit Angiogenesis and Choroidal Neovascularization in Mice

Tissue Inhibitor of Metalloproteinases-3 Peptides Inhibit Angiogenesis and Choroidal Neovascularization in Mice

Atypical Sorsby Fundus Dystrophy With a Novel Tyr159cys Timp-3 Mutation

A Novel Mutation at the N-Terminal Domain of the Timp3 Gene in Sorsby Fundus Dystrophy

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