Background: The recent identification of the tissue inhibitor of metalloproteinases-3 (TIMP3) as the gene underlying SFD pathology has made it possible to address the question of genetic heterogeneity in this disorder. In addition, it now has become feasible to clarify whether SFD is directly involved in other maculopathies and, in particular, may represent a genetic model for age-related macular degeneration.
Patients: Genetic analysis were performed in five unrelated and 18 related British SFD pedigrees as well as in 143 patients affected with age-related macular degeneration, 28 patients with adult vitelliform macular dystrophy, 21 patients with central areolar choroidal dystrophy and 25 individuals with other forms of macular dystrophies.
Results: Molecular genetic analyses confirmed the autosomal dominant mode of inheritance in SFD. In all five unrelated SFD pedigrees individual TIMP3 mutations were identified introducing an additional cysteine residue into the C-terminal region of the mature protein. Affected individuals from 18 SFD families residing in Great Britain, Canada, Oregon and South Africa were found to carry a common ancestral Ser181Cys mutation. The clinical variability of this Ser181Cys mutation was reevaluated. A mutational screen in 217 patients with various maculopathies revealed no disease-causing mutations in the TIMP3 gene.
Conclusion: So far, TIMP3 mutations have exclusively been associated with SFD. Therefore, this disorder appears to be genetically homogeneous with complete penetrance but variable expressivity.