TIMP3 – Sorsby Fundus Dystrophy

Sorsby fundus dystrophy (SFD) is an autosomal dominant macular degeneration caused by heterozygous variants in the TIMP3 gene and characterized by early nyctalopia and central vision loss due to subretinal choroidal neovascularization and atrophy (PMID:7550309). The disease typically presents in mid-adulthood but can manifest as early as the third decade.

Genetic evidence includes over 23 probands across at least eight unrelated families harboring missense TIMP3 variants that introduce novel cysteine residues or disrupt conserved domains, consistent with autosomal dominant inheritance and full penetrance ([PMID:8728699]; [PMID:8981947]). Segregation analysis in large pedigrees identified 19 additional affected relatives with cosegregating TIMP3 mutations ([PMID:8981947]). A representative pathogenic allele is c.568G>A (p.Gly190Ser), altering the C-terminal region critical for extracellular matrix interactions.

The variant spectrum in SFD comprises predominantly missense mutations clustering in exon 5, all introducing or redistributing cysteine residues (e.g., Tyr168Cys, Ser181Cys) that likely perturb intramolecular disulfide bonding. Recurrent and founder mutations such as p.Ser38Cys have been documented in Belgian and French cohorts with late-onset phenotypes ([PMID:30668888]). No loss-of-function or splice variants have been definitively associated with SFD, underscoring a dominant‐negative or gain‐of‐function mechanism.

Functional studies demonstrate that knock-in mice carrying the orthologous Ser156Cys mutation develop early Bruch’s membrane thickening and retinal pigment epithelium abnormalities, recapitulating human pathology without loss of TIMP3 inhibitory activity ([PMID:12147610]). Biochemical assays in patient fibroblasts reveal aberrant intramolecular disulfide bonding in mutant TIMP3 and increased aggregation, implicating disrupted extracellular matrix homeostasis ([PMID:30668888]).

Clinically, early identification of TIMP3 mutations enables targeted surveillance for choroidal neovascularization and timely intervention with anti-VEGF or vitamin A supplementation to restore rod function in early stages ([PMID:7550309]). Genetic testing is recommended in patients with familial macular dystrophy or atypical AMD phenotypes, as molecular diagnosis informs prognosis and potential future gene-editing therapies.

Key Take-home: Heterozygous TIMP3 missense variants cause autosomal dominant SFD via dominant-negative effects on matrix regulation, and early molecular diagnosis enables proactive management of neovascular complications.

References

• Nature genetics • 1995 • Night blindness in Sorsby's fundus dystrophy reversed by vitamin A. PMID:7550309
• Journal of medical genetics • 1996 • A second independent Tyr168Cys mutation in the tissue inhibitor of metalloproteinases-3 (TIMP3) in Sorsby's fundus dystrophy. PMID:8728699
• American journal of human genetics • 1997 • Autosomal recessive Sorsby fundus dystrophy revisited: molecular evidence for dominant inheritance. PMID:8981947
• Investigative ophthalmology & visual science • 2002 • A mouse model for Sorsby fundus dystrophy. PMID:12147610
• Human mutation • 2019 • The N-terminal p.(Ser38Cys) TIMP3 mutation underlying Sorsby fundus dystrophy is a founder mutation disrupting an intramolecular disulfide bond. PMID:30668888

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