Evaluation of the gene encoding the tissue inhibitor of metalloproteinases-3 in various maculopathies.

PURPOSE Mutations in the gene encoding the tissue inhibitor of metalloproteinases-3 (TIMP3) have been shown previously to cause Sorsby's fundus dystrophy, an autosomal-dominant disorder characterized by extracellular matrix irregularities in Bruch's membrane. To assess the involvement of TIMP3 in a variety of other macular dystrophies, the authors have screened this gene for disease-causing mutations in age-related macular degeneration (AMD), adult vitelliform macular dystrophy (AVMD), central areolar choroidal dystrophy (CACD), syndrome-associated macular dystrophies, cone-rod dystrophy, and a group with unspecified macular degeneration. METHODS Single-stranded conformational analysis of the entire coding region was performed using the polymerase chain reaction and oligonucleotide primers flanking the five exons of the TIMP3 gene as well as the putative promotor region and a highly conserved fragment of the 3'-untranslated region. The authors analyzed a total of 217 patients, including 143 patients with AMD, 28 patients with AVMD, 21 patients with CACD, and 25 patients with other forms of macular dystrophy. RESULTS In the 217 patients analyzed, the authors have identified one sequence alteration (a G-to-C base change) in the 5'-untranslated region in a patient with AMD. However, the functional consequences of this mutation are not clear. No other disease-causing mutations were found. The authors have characterized a frequent intragenic polymorphism in exon 3 of the TIMP3 gene (heterozygosity = 0.57) that will be useful for genetic linkage or allele sharing analyses or both. CONCLUSIONS The authors' results suggest that TIMP3 is not a major factor in the cause of AMD, AVMD, and CACD. Thus far, Sorsby's fundus dystrophy appears to be the only phenotype known to be associated with mutations in TIMP3.