Are 2 disease-associated TIMP3 variants in the signal peptide sequence associated with cleavage and extracellular TIMP3 localization, representing a potentially new disease mechanism?
In this case series of 2 families, 2 likely pathogenic variants, c.29T>A p.(Leu10His) and c.34G>C p.(Gly12Arg), located in the signal peptide sequence, were found to segregate with macular dystrophy. These 2 variants are involved in protein trafficking defects associated with failure of secretion into extracellular matrix.
These results suggest atypical patient presentations are caused by TIMP3 signal peptide defects, associated with impaired cleavage and secretion, implicating a distinct macular dystrophy disease mechanism.
Sorsby fundus dystrophy is a typically adult-onset maculopathy with high risk for choroidal neovascularization. Sorsby fundus dystrophy, inherited as an autosomal dominant fully penetrant trait, is associated with TIMP3 variants that cause protein aggregation in the extracellular matrix.
To evaluate the phenotype and underlying biochemical mechanism of disease-causing TIMP3 variants altering the N-terminal signal peptide in 2 families who have early-onset diffuse maculopathy without choroidal neovascularization with cosegregation of TIMP3 variants in the signal peptide sequence.
Design, Setting, and Participants
This case series of 2 families with early-onset diffuse maculopathy was conducted at the National Eye Institute, National Institutes of Health Clinical Center. Data were collected and analyzed from October 2009 to December 2021.
Main Outcomes and Measures
Clinical imaging and molecular genetic testing were performed in 2 families with macular dystrophy. Cosegregation analysis of TIMP3 variants was performed in affected and unaffected family members. Candidate TIMP3 signal peptide variants were assessed for cleavage defects after transfection.
Eleven individuals from 2 families with early-onset diffuse maculopathy without choroidal neovascularization harbor TIMP3 variants (L10H or G12R) in the N-terminal signaling peptide were analyzed. Cosegregation with phenotype was confirmed in additional family members. Biochemical analysis confirmed defects in both protein maturation and extracellular deposition.
Conclusions and Relevance
This study found that TIMP3 variants altering signal peptide function deviated from classic Sorsby fundus dystrophy both in phenotypic features and underlying mechanism. These results suggest atypical patient presentations are caused by TIMP3 signal peptide defects, associated with impaired cleavage and deposition into the extracellular matrix, implicating a novel macular dystrophy disease.
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Guan B, Huryn LA, Hughes AB, et al. Early-Onset TIMP3-Related Retinopathy Associated With Impaired Signal Peptide. JAMA Ophthalmol. 2022;140(7):730–733. doi:10.1001/jamaophthalmol.2022.1822
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