Sorsby Fundus Dystrophy in an Asian Pedigree: Pathogenic Timp3 P.Y191c Variant Impairs Its Binding with Mmp2/9 and...

To characterize the clinical phenotype and elucidate the pathogenic mechanism of the novel TIMP3 p.Y191C variant in a multigenerational Asian pedigree with Sorsby Fundus Dystrophy (SFD).

Affected family members underwent comprehensive ophthalmic evaluations. Genetic analysis was performed via whole-exome and Sanger sequencing. An ARPE-19 cell models overexpressing wild-type or mutant TIMP3 were generated. Functional analysis including co-immunoprecipitation (Co-IP), MMP inhibition, and immunofluorescence were performed.

A heterozygous TIMP3 p.Y191C variant was identified in seven affected members, co-segregating with bilateral choroidal neovascularization and disciform scarring. The tyrosine-191 residue is highly conserved, and structural/computational analyses predicted that the cysteine substitution introduces a smaller, hydrophobic residue and reduces protein stability. Functionally, the Y191C variant impaired TIMP3 binding to MMP2 and MMP9, reduced its inhibitory activity, and altered MMP2 localization following LPS stimulation. Consistent with this loss of function, the mutant TIMP3 significantly inhibited cell viability and promoted apoptosis in ARPE-19 cells under inflammatory stress.

The novel TIMP3 p.Y191C variant causes SFD in an Asian pedigree. Its pathogenicity arises from distinct disruptions in MMP2/9 binding and inhibition, coupled with altered MMP2 localization, thereby providing a mechanistic basis for the disease.