Increased expression of TIMP-3 is also observed in other degenerative retinal diseases, including the more severe forms of age-related macular degeneration, the most common cause of blindness in the elderly in developed countries.
We found that the expression level of LIPC, SLC16A8, and TIMP-3 was significantly associated with AMD pathology in both groups (LIPC: P = 0.008, SLC16A8: P < 0.001, TIMP-3: P < 0.001, respectively).
Interestingly, we observed increased expression of tissue inhibitor of metalloproteinase 3 (Timp3) during the aging process, a gene associated with AMD and Bruch's membrane integrity.
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.
Our results were supported by significant accumulation and expression overlap of both TIMP-3 and EFEMP1 between the retinal pigment epithelia and Bruch membrane in the eyes of ML and AMD patients.
We also discuss briefly how, despite the lack of inherited mutations in the structural gene, the TIMP3 protein might play a role in the onset and progression of AMD.
Recently, two genome-wide association studies with large cohorts both identified rs9621532, a new single nucleotide polymorphism (SNP) that is associated with advanced age-related macular degeneration (AMD) and located near the TIMP3 gene.
These results provide new insights into the pathogenesis of SFD and other retinopathies linked to mutations in TIMP3, such as age-related macular degeneration.
With the sample size of our study, no relationship was found for AMD and the SNPs tested in complement 3 (C3); serpin peptidase inhibitor, clade G, member 1 (SERPING1); vascular endothelial growth factor (VEGF); cholesterol ester transfer protein (CETP); lipoprotein lipase (LPL); hepatic lipase (LIPC); and metallopeptidase inhibitor 3 (TIMP3) genes.
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.
A recent genome-wide 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.
Understanding the molecular functions of wild-type and mutant TIMP3 will provide significant insights into the patho-physiology of SFD and perhaps AMD.
We also discuss briefly how, despite the lack of inherited mutations in the structural gene, the TIMP3 protein might play a role in the onset and progression of AMD.