A 2ND INDEPENDENT TYR168CYS MUTATION IN THE TISSUE INHIBITOR OF METALLOPROTEINASES-3 (TIMP3) IN SORSBY FUNDUS DYSTROPHY

Sorsby's fundus dystrophy (SFD) is a rare autosomal dominant macular d isorder with age of onset usually in the fourth decade. It is characte rised by loss of central vision owing to subretinal neovascularisation and disciform macular degeneration. In an effort to identify the SFD gene, the disease locus was first mapped to chromosome 22q13-qter by g enetic linkage analysis, the same chromosomal region as the gene encod ing the tissue inhibitor of metalloproteinases-3 (TIMP3). Subsequently , two separate mutations in TIMP3 were found in affected members of tw o unrelated SFD pedigrees (Tyr168Cys and Ser181Cys). More recently, tw o additional SFD related mutations, Ser156Cys and Gly167Cys, have prov ided further confirmation that heterozygous mutations in TIMP3 are cau sally responsible for the SFD phenotype. We now report the occurrence of the Tyr168Cys mutation in an SFD patient of Austrian descent and sh ow that this mutation found earlier in an American SFD family arose in dependently. The new findings add to an emerging pattern of SFD mutati ons which all seem to affect the C-terminal region of the mature TIMP3 protein. In addition, all known mutations cause a change of an amino acid to a cysteine residue. This suggests a critical role for the addi tional C-terminal free thiol group in SFD pathogenesis.