NEI researchers discover potential new type of macular dystrophy
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Researchers from the National Eye Institute found TIMP3 variants cause atypical presentations of Sorsby fundus dystrophy, potentially indicating a different type of macular dystrophy not previously classified.
Sorsby fundus dystrophy (SFD) is associated with pathogenic variants of the TIMP3 gene evidenced by drusen and accumulations in the subretinal pigment epithelial space. It typically presents in adulthood with night blindness and visual acuity changes secondary to choroidal neovascularization.
In two families, two likely pathogenic variants of TIMP3, c.29T>A p.(Leu10His) and c.34G>C p.(Gly12Arg), were found to be associated with atypical presentations. All affected individuals had diffuse maculopathy, with predominantly paracentral atrophy resulting in paracentral scotomas. Central vision was preserved, and no choroidal neovascularization was present, even in individuals with long-standing diagnoses of more than 20 years. In addition, while the normal age of onset is between the third and the fifth decade, half of the affected subjects manifested the signs and symptoms of the disease in the second decade.
“Given that individuals with TIMP3 signal peptide variants did not show hemorrhage or neovascularization often observed in classic SFD, we postulated that the two variants represent a different disease mechanism for TIMP3-related retinopathy by altering protein trafficking,” the authors wrote.
This hypothesis was tested, and data showed that both variants cause TIMP3 signal peptide defect, impairing cleavage and secretion and causing the protein to be retained in the cell, likely leading to retinal pigment epithelium toxicity.
“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,” Robert B. Hufnagel, MD, PhD, senior author and director of the Ophthalmic Genomics Laboratory at NEI, said in an NEI press release.
Reference:
- NIH researchers discover new genetic eye disease. https://www.nih.gov/news-events/news-releases/nih-researchers-discover-new-genetic-eye-disease. Published June 9, 2022.
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