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.

Sorsby fundus dystrophy (SFD) is a rare autosomal dominant disease with complete penetrance and great variability even within the same mutation.

A diagnosis of age-related macular degeneration (AMD) may have a significant impact on a patient's life. Therefore, it is important to consider differential diagnoses, as these can differ considerably from AMD regarding prognosis, inheritance, monitoring and therapy. Differential diagnoses include other macular diseases with drusen, drusen-like changes, monogenic retinal dystrophies, as well as a wide range of other, often rare macular diseases. In this review, clinical examples are presented that illustrate alternative diagnoses to AMD and when these should be considered. These include, amongst others, patients with autosomal dominant drusen, Sorsby fundus dystrophy, pachydrusen, late-onset Stargardt disease, extensive macular atrophy with pseudodrusen (EMAP), pseudoxanthoma elasticum (PXE), North Carolina macular dystrophy, mitochondrial retinopathy, benign yellow dot maculopathy, dome- or ridge-shaped maculopathy, or macular telangiectasia type 2. Die Diagnose der altersabhängigen Makuladegeneration (AMD) kann einen Einschnitt im Leben von Patienten bedeuten. Vor diesem Hintergrund ist es wichtig, Differenzialdiagnosen in Erwägung zu ziehen, da diese sich hinsichtlich Prognose, Vererblichkeit, Kontroll- und Therapiebedarf beträchtlich von der AMD unterscheiden können. Differenzialdiagnosen sind vor allem andere Makulaerkrankungen mit Drusen, drusenähnlichen Veränderungen, weitere monogene Netzhautdystrophien sowie ein breites Spektrum weiterer, oftmals seltener Makulaerkrankungen. In dieser Übersicht werden anhand klinischer Beispiele Befundkonstellationen gezeigt, bei denen eine Differenzialdiagnose der AMD in Erwägung gezogen werden sollte. Unter anderem beinhaltet dies Patienten mit autosomal-dominanten Drusen, Sorsby-Fundusdystrophie, Pachydrusen, spät beginnendem Morbus Stargardt, extensive makuläre Atrophie mit Pseudodrusen (EMAP), Pseudoxanthoma elasticum (PXE), North-Carolina-Makuladystrophie, mitochondriale Retinopathie, Benign Yellow Dot Maculopathy, kuppel- oder leistenförmige Makulopathie und makuläre Teleangiektasien Typ 2.

Metabolic defects in the retinal pigment epithelium (RPE) underlie many retinal degenerative diseases. This study aims to identify the nutrient requirements of healthy and diseased human RPE cells. We profiled nutrient use of various human RPE cells, including differentiated and dedifferentiated fetal RPE (fRPE), induced pluripotent stem cell-derived RPE (iPSC RPE), Sorsby fundus dystrophy (SFD) patient-derived iPSC RPE, CRISPR-corrected isogenic SFD (cSFD) iPSC RPE, and ARPE-19 cell lines using Biolog Phenotype MicroArray Assays. Differentiated fRPE cells and healthy iPSC RPE cells can use 51 and 48 nutrients respectively, including sugars, intermediates from glycolysis and tricarboxylic acid (TCA) cycle, fatty acids, ketone bodies, amino acids, and dipeptides. However, when fRPE cells lose their epithelial phenotype through dedifferentiation, nutrient use becomes restricted to 17 nutrients, primarily sugar and glutamine-related amino acids. SFD RPE cells can use 37 nutrients; however, compared to cSFD RPE and healthy iPSC RPE, they are unable to use lactate, some TCA cycle intermediates, and short-chain fatty acids. Nonetheless, they show increased use of branch-chain amino acids (BCAAs) and BCAA-containing dipeptides. Dedifferentiated ARPE-19 cells grown in traditional culture media cannot use lactate and ketone bodies. In contrast, nicotinamide supplementation promotes differentiation toward an epithelial phenotype, restoring the ability to use these nutrients. Epithelial phenotype confers metabolic flexibility to healthy RPE for using various nutrients. SFD RPE cells have reduced metabolic flexibility, relying on the oxidation of BCAAs. Our findings highlight the potentially important roles of nutrient availability and use in RPE differentiation and diseases.

Sorsby fundus dystrophy (SFD) is a rare autosomal dominant disorder with macular dystrophy and severe visual loss. Mutations in TIMP3 gene has been related to SFD with mechanisms unclear. We have successfully reprogrammed the peripheral blood mononuclear cells (PBMCs) from an SFD patient carrying c.484G>A mutation in TIMP3 gene to induced pluripotent stem cells (iPSCs) and characterized their pluripotency and genetic stability. This line may serve as a useful tool to explore the role of TIMP3 in SFD pathogenesis.