A NOVEL SPLICE-SITE MUTATION IN THE TISSUE INHIBITOR OF THE METALLOPROTEINASES-3 GENE IN SORSBYS-FUNDUS-DYSTROPHY WITH UNUSUAL CLINICAL-FEATURES

Sorsby's fundus dystrophy (SFD) is an autosomal dominant macular dystr ophy which is developed usually in the third or fourth decade of life, and is characterized by central visual loss and nyctalopia due to fun dus changes of exudative or atrophic macular lesions. Its functional p rognosis is usually poor because of disciform macular scars and periph eral chorioretinal atrophies. To date, five different mutations in the tissue inhibitor of the metalloproteinases-3 (TIMP3) gene have been i dentified in families of a wide geographic origin, all of which are mi ssense mutations that cause replacement by cysteine of conserved amino acids in the C-terminus of exon 5 of TIMP3. We have studied two Japan ese families with SFD, the first report from the Eastern world, and id entified a novel 3' splice site mutation in the TIMP3 gene, namely a s ingle base insertion at the intron 4/exon 5 junction which converts th e consensus sequence CAG to CAAG in the splice acceptor site. In addit ion, our patients displayed a distinctive clinical expression in that they developed macular dystrophies at an approximately 30-year later a ge of onset and preserved functional vision until later life with esse ntially uninvolved peripheral retina. The present findings may provide some insight into the genotype-phenotype relationship in SFD.