A Novel His158Arg Mutation in TIMP3 Causes a Late-Onset Form of Sorsby Fundus Dystrophy

Lin, Ruth; Blumenkranz, Mark S.; Binkley, Jonathan; Wu, Kathy H C; Vollrath, Douglas

doi:10.1016/j.ajo.2006.06.003

Cited by 30 publications

(31 citation statements)

References 44 publications

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“…1 It causes early onset central vision loss from exudative maculopathy and/or atrophic macular lesions. 2 Peripheral vision loss and nyctalopia may also occur. Findings of physical examination reveal drusenlike deposits throughout the retina, atrophy of the photoreceptors and retinal pigment epithelium (RPE), choroidal neovascularization (CNV), and disciform scarring.…”

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confidence: 98%

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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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confidence: 98%

“…3 Sorsby fundus dystrophy is caused by a mutation in the tissue inhibitor of metalloproteinase 3 (TIMP3) gene. 2 This gene encodes a protein that is secreted by the RPE and deposited in Bruch membrane, and it is involved in the maintenance of the extracellular matrix. 4 It also inhibits angiogenesis 5 and regulates inflammation.…”

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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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“…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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“…One study however, reported loss of MMP inhibition and lack of dimerization of S156C-TIMP3 when overexpressed in ARPE-19 cells (Qi et al, 2002). Moreover, two SFD-linked mutations (H158R, E139K) (Lin et al, 2006;Sarra and WolfSchnurrbusch, personal communication) obviously fail to generate an unpaired cysteine residue possibly indicating a disease mechanism that may be independent from disulfide-mediated oligomerization. Immunohistology on human donor eyes with SFD showed an excessive amount of TIMP3 protein in Bruch's membrane deposits (Fariss et al, 1998;Chong et al, 2000).…”

Section: Introductionmentioning

confidence: 92%

Molecular dissection of TIMP3 mutation S156C associated with Sorsby fundus dystrophy

et al. 2008

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A Novel His158Arg Mutation in TIMP3 Causes a Late-Onset Form of Sorsby Fundus Dystrophy

Cited by 30 publications

References 44 publications

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

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

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

Molecular dissection of TIMP3 mutation S156C associated with Sorsby fundus dystrophy

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