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G.-M. Sarra, C. A. Suter, S. Gallati, S. Wolf, U. Wolf-Schnurrbusch; Novel TIMP3 Mutation (Glu139Lys) in a Large Swiss Pedigree With Sorsby Fundus Dystrophy. Invest. Ophthalmol. Vis. Sci. 2007;48(13):1670.
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Sorsby's fundus dystrophy (SFD) is an autosomal-dominant dystrophy of the central retina, characterized by extracellular deposits (drusen) and thickening of Bruch's membrane. At later stages choroidal neovascularisation (CNV) and/or atrophy of the choriocapillaris-RPE-complex develop with high incidence. SFD is caused by mutations in the "tissue inhibitor of metalloproteinases 3" (TIMP3) gene. Here we present a genotype-phenotype characterization of a four-generation Swiss pedigree with hereditary fundus dystrophy.
Mutation analysis was carried out in 51 family members using single strand conformation polymorphism (SSCP) and DNA sequence analyses of the suspected candidate gene, TIMP3. Phenotype characterization was performed using standard 30 degree fundus photography, which were graded into the following stages: 0: normal, I: individual drusen, II: confluent drusen, III: choroidal neovascularisation (CNV), and IV: chorioretinal atrophy.
56 living family members agreed to participate - 46 in both the clinical and molecular examinations, five in the molecular and five in the clinical examinations only. We detected a novel Glu139Lys mutation in exon five of the TIMP3 gene segregating in an autosomal-dominant pattern. Of the 13 individuals heterozygous for this mutation, 11 (84.6%) had a retinal phenotype: isolated drusen (stage I) were found in six eyes of four mutation carriers (mean age 33.7, range 23-42 yrs): confluent drusen (stage II) were detected in six eyes of four patients (mean age 48.7, range 39-64 yrs). Eight eyes of five patients showed a subfoveolar CNV (stage III) with a mean age of onset at 42 (range 34-50 yrs). Chorioretinal atrophy (stage IV) was found in five eyes of three individuals (mean age 68.6, range 56-86 yrs). The two teenagers carrying the mutation did not show any evidence of retinal lesions.
Our family expresses an age-dependent phenotype beginning with individual drusen in the 3rd decade of life, which become confluent and abundant at later stages. CNV follows with a very high incidence in the fifth decade. Five different mutations have previously been identified, four of them introducing an extra cysteine residue into exon 5. The Glu139Lys mutation reported here is the first introducing a lysine residue. This Mendelian disease provides a model for the study of the genetically complex age-related macular degeneration.
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