title: Tissue inhibitor of metalloproteinases-3 (TIMP-3) is a binding partner of epithelial growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1). Implications for macular degenerations.
abstract: Tissue inhibitor of metalloproteinases-3 (TIMP-3) is a matrix-bound inhibitor of matrix metalloproteinases. Mutations in the Timp-3 gene cause Sorsby fundus dystrophy (SFD), a hereditary macular degenerative disease. The pathogenic mechanisms responsible for the disease phenotype are unknown. In an in vivo quest for binding partners of the TIMP-3 protein in the subretina, we identified epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1, also known as fibulin 3) as a strong interacting protein. The COOH-terminal end of TIMP-3 was involved in the interaction. Interestingly, a missense mutation in EFEMP1 is responsible for another hereditary macular degenerative disease, Malattia Leventinese (ML). Both SFD and ML have strong similarities to age-related macular degeneration (AMD), a major cause of blindness in the elderly population of the Western hemisphere. 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. These results provide the first link between two different macular degenerative disease genes and imply the possibility of a common pathogenic mechanism behind different forms of macular degeneration.
authors.affiliation: Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Klenotic
authors.forename: Francis L
authors.initials: FL
authors.lastname: Munier
authors.forename: Lihua Y
authors.initials: LY
authors.lastname: Marmorstein
authors.forename: Bela
authors.initials: B
authors.lastname: Anand-Apte
mesh_terms: D000818:Animals; D002460:Cell Line; D018076:DNA, Complementary / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000737:chemistry* / Q000378:metabolism; D005822:Genetic Vectors; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008268:Macular Degeneration / Q000235:genetics; D008957:Models, Genetic; D020125:Mutation, Missense; D010857:Pigment Epithelium of Eye / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D012160:Retina / Q000378:metabolism; D013552:Swine; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D020798:Two-Hybrid System Techniques
chemical_list: D018076:DNA, Complementary; C119630:EFEMP1 protein, human; D016326:Extracellular Matrix Proteins; D019717:Tissue Inhibitor of Metalloproteinase-3; D005982:Glutathione Transferase