Sorsby's fundus dystrophy (SFD) is caused by mutations in tissue inhibitor of metalloproteinase (TIMP)‐3 and, with the exception of early onset, is similar to age‐related macular degeneration. The pathological features of this condition relate to the accumulation of TIMP‐3 in Bruch's membrane.
To compare the extracellular membrane‐binding characteristics of wild‐type and four SFD‐mutant TIMP‐3s.
COS‐7 cells were transfected with wild‐type, Ser‐181, Gly‐167, Ser‐156 and Tyr‐168 SFD‐mutant TIMP‐3 cDNA. The TIMP‐3 proteins subsequently synthesised were harvested, analysed by sodium dodecyl sulphate‐polyacrylamide gel electrophoresis, semiquantified by ELISA and used in binding assays on the basis of the retention of the wild‐type and SFD‐mutant TIMP‐3 proteins by components of Bruch's membrane.
SFD‐mutant TIMP‐3s could not be distinguished from wild‐type TIMP‐3 by the extents to which they aggregated or adhered to type‐I collagen, type‐IV collagen, fibronectin, laminin, elastin, chondroitin sulphates A, B and C, and heparin sulphate. Of these macromolecules, the wild‐type and SFD‐mutant TIMP‐3s exhibited greatest affinity for elastin and laminin.
The similarity in the physical and extracellular membrane‐binding characteristics of wild‐type and SFD‐mutant TIMP‐3s indicates that these properties are not responsible for the difference in timing of onset of SFD and age‐related macular degeneration.