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Atypical TIMP3 defects may present a distinct disease mechanism of Sorsby Fundus Dystrophy.

Researchers based at the NEI’s Ophthalmic Genomics Laboratory, National Eye Institute, Bethesda, have reported anomalous TIMP3 variants with altering signal peptide function, distinct from classic Sorsby fundus dystrophy (SFD).  The study showed atypical patient presentations caused by TIMP3 signal peptide defects, and associated with impaired cleavage and deposition into the extracellular matrix (ECM).  Researchers conclude that the description may identify a novel macular dystrophy disease and may provide valuable information to comprehensively diagnose other similar patients.


While a number of certain macular dystrophies show heterogeneous disorders caused by variants of ABCA4, BEST1, PRPH2, TIMP3 and others, pathogenic variants in TIMP3 in the literature are associated with Sorsby fundus dystrophy. In their recent report in JAMA Ophthalmology (x), SFD is generally evidenced by drusen and accumulations in the subretinal pigment epithelial space, and in addition, patients have adult-onset pathologies with night blindness and acute changes in visual acuity secondary to choroidal neovascularization. As well described, the TIMP3 gene encodes tissue inhibitor of metalloproteinases-3, which is secreted from the RPE and incorporated into the Bruch membrane.  The majority of TIMP3 mature protein variants are present in the C-terminal domain and introduce an additional cysteine, leading to accumulation of variant protein in the extracellular matrix (ECM). However, two (2) families affected by macular dystrophy associated with variants in the TIMP3 signal peptide shows a lack of these classic features of SFD.


In the recent study, and in contrast the to this more classical SFD description, eleven (11) individuals from two families showed early-onset diffuse maculopathy, without choroidal neovascularization (CNV), and with TIMP3 variants in the N-terminal signalling peptide.  The likely pathogenic TIMP3 variants reported c.29T>A p.(Leu10His) and c.34G>C p.(Gly12Arg), located in the signal peptide sequence. The data were collected and analyzed from October 2009 to December 2021 and co-segregation of the phenotype was confirmed in additional family members. In their analysis, one of the researchers, Cathy Cukras, M.D., Ph.D., stated that, “affected individuals had scotomas, or blind spots, and changes in their maculae indicative of disease, but, for now, they have preserved central vision and no choroidal neovascularization, unlike typical Sorsby Fundus Dystrophy”.  Finally, the leading author of the report, and director of the Ophthalmic Genomics Laboratory at NEI, Rob Hufnagel, M.D., Ph.D., said that, “discovering novel disease mechanisms, even in known genes like TIMP3, may help patients that have been looking for the correct diagnosis, and will hopefully lead to new therapies for them”.