This review summarizes the current knowledge on TIMP3 and how mutations in TIMP3 cause SFD to provide insights into how we can study this disease going forward.
Thus, understanding the molecular mechanisms that contribute to CNV as a consequence of TIMP-3 mutations will provide insight into the pathophysiology in SFD and likely the neovascular component of the more commonly seen AMD.
It has been demonstrated that SFD-associated TIMP3 variants are more resistant to turnover, which is thought to be a result of dimerisation and thought to explain the accumulation of TIMP3 in drusen-like deposits at the level of Bruch's membrane.
All were later found to carry a predicted C113G mutation in the TIMP3 gene, other known mutations in which are associated with Sorsby's fundus dystrophy.
To report novel TIMP3 mutations, and to characterize the ocular phenotype of Sorsby fundus dystrophy (SFD), including a novel early sign for the disease and to report the effect of anti-VEGF therapy.
TIMP3 novel variants were found in two SFD patients, PRPH2 variants in 14 PD patients, ABCA4 variants in four PD patients, and p.Arg838His GUCY2D mutation in six patients diagnosed with dominant CRD; one patient additionally had a CRX VUS.
First, genetically engineered mice that target genes related to juvenile macular dystrophies are the most common models, and they include abcr(-/-) (Stargardt disease), transgenic ELOVL4 (Stargardt-3 dominant inheritary disease), Efemp1(R345W/R345W) (Doyne honeycomb retinal dystrophy), and Timp3(S156C/S156C) (Sorsby fundus dystrophy) mice.
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.
These data show that increased deposition of active TIMP-3, rather than dysregulation of metalloproteinase inhibition, is likely to be the primary, initiating event in SFD.
This review confines itself to a discussion of the known biochemical properties of the wild-type and SFDTIMP3 proteins and attempts to relate these to the pathology encountered in SFD patients.
TIMP3, which encodes a potent angiogenesis inhibitor, is mutated in Sorsby fundus dystrophy, a macular degenerative disease with submacular choroidal neovascularization.
Increased expression of TIMP-3 mRNA does not cause accumulation of TIMP-3 in the Bruch membrane of Sorsby fundus dystrophy nor is it likely to cause age-related macular degeneration.
Sorsby fundus dystrophy (SFD) is a rare, late-onset macular dystrophy caused by mutations in the tissue inhibitor of metalloproteinases-3 (TIMP3) gene.