A Novel Hi158Arg Mutation in TIMP3 Caue a Late-Onet Form of orby Fundu Dytrophy Original Reearch Article

Purpoe To decribe the phenotype and genotype of a family with upected orby fundu dytrophy (FD). Deign Cae report and reult of deoxyribonucleic acid (DNA) analyi. Method Clinical feature were determined by complete ophthalmologic examination or by review of medical record. Mutational analyi of the tiue inhibitor of metalloproteinae (TIMP)3 gene wa performed by DNA reequencing. Biochemical propertie of the mutant TIMP3 protein were tudied, and phylogenetic and molecular modeling analye of TIMP protein were performed. Reult Fundi of four affected family member demontrated active or regreed bilateral choroidal neovacularization, wherea another affected individual diplayed evere diffue pigmentary degeneration aociated with nyctalopia characteritic of FD. Onet of dieae occurred in the fifth to eventh decade of life. A heterozygou Hi158Arg mutation wa found in even affected family member and wa abent from an unaffected member and 98 unrelated control. Bioinformatic analye indicate that hitidine 158 i an evolutionarily conerved reidue in mot vertebrate TIMP homolog and predict that ubtitution by arginine dirupt TIMP3 function. The mutant protein appear to be expreed by fibroblat from an affected family member. Molecular modeling ugget that TIMP3 reidue 158 may be part of a protein-protein interaction interface. Concluion A novel mutation in TIMP3 caue a late-onet form of FD in thi family. Hi158Arg i the firt reported TIMP3 FD coding equence mutation that doe not create an unpaired cyteine. Further tudy of thi unuual mutation may provide inight into the mechanim of FD pathogenei.