title: Sorsby's fundus dystrophy mutant tissue inhibitors of metalloproteinase-3 induce apoptosis of retinal pigment epithelial and MCF-7 cells.
abstract: C-terminal domain tissue inhibitor of metalloproteinases-3 (TIMP-3) mutations cause the rare hereditary blindness Sorsby's fundus dystrophy (SFD), which involves loss of retinal pigment epithelial (RPE) cells. Since wild-type TIMP-3 causes apoptosis, we investigated whether SFD TIMP-3 might kill RPE and other cells. Plasmid-mediated overexpression of Ser-156, Gly-167, Tyr-168 and Ser-181 SFD mutant TIMP-3 decreased RPE viability to 22+/-8, 20+/-6, 32+/-5, 30+/-12% (SFD mutants all P<0.01 versus wild-type 50+/-8%) and similarly increased propidium iodide staining and in situ end labelling. Adenovirus-mediated overexpression of the Gly-167 mutant also caused RPE apoptosis dose-dependently. Apoptosis of RPE cells might therefore contribute to the pathology of SFD.
authors.affiliation: Institute of Ophthalmology, University of Bristol, Bristol Eye Hospital, Lower Maudlin Street, Bristol BS1 2LX, UK.
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Majid
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Smith
authors.forename: David L
authors.initials: DL
authors.lastname: Easty
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Baker
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Newby
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D005654:Fundus Oculi; D006801:Humans; D010857:Pigment Epithelium of Eye / Q000166:cytology / Q000378:metabolism*; D012164:Retinal Diseases / Q000378:metabolism*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000737:chemistry / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D019717:Tissue Inhibitor of Metalloproteinase-3