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Researchers from the National Eye Institute (NEI) have identified a new disease that affects the macula, a small light-sensitive part of the retina necessary for sharp central vision. Scientists report their findings on the new, as yet unnamed macular dystrophy in JAMA Ophthalmology. NEI is part of the National Institutes of Health.

Macular dystrophies are disorders that typically cause central vision loss due to mutations in several genes, including ABCA4, BEST1, PRPH2, and TIMP3.

For example, patients with Sorsby’s fundus dystrophy, a genetic eye disease specifically linked to TIMP3 variants, typically develop symptoms in adulthood. They often present with sudden changes in visual acuity due to choroidal neovascularization – new abnormal blood vessels that grow under the retina, leaking fluid and affecting vision.

TIMP3 is a protein that helps regulate retinal blood flow and is secreted by the retinal pigment epithelium (RPE), a layer of tissue that nourishes and supports light-sensitive photoreceptors in the retina. All reported TIMP3 gene mutations are found in the mature protein after it has been “cut” from RPE cells in a process called cleavage.

“We found it surprising that two patients had TIMP3 variants not in the mature protein, but in the short signal sequence the gene uses to ‘cut’ the protein from cells. We showed that these variants prevent cleavage, causing the blockage of the protein in the cell, likely resulting in retinal pigment epithelial toxicity,” said Bin Guan, Ph.D., lead author.

The research team followed up these findings with clinical evaluations and genetic testing of family members to verify that the two new TIMP3 variants are linked to this atypical maculopathy.

“Affected individuals had scotomas, or blind spots, and changes in their macules indicative of disease, but, so far, they have retained central vision and no choroidal neovascularization, unlike typical fundus dystrophy. Sorsby’s eye,” said Cathy Cukras, MD, Ph.D., a tenure-track Lasker researcher and medical retina specialist who clinically assessed patients.

NEI’s Ophthalmic Genomics Laboratory collects and manages specimens and diagnostic data from patients who have been recruited into multiple studies as part of NEI’s clinical program to facilitate research into rare ocular diseases, including fundus dystrophy of Sorsby.

“Discovering new disease mechanisms, even in known genes like TIMP3, can help patients who have been searching for the right diagnosis and will hopefully lead to new therapies for them,” said Rob Hufnagel, MD, Ph.D. ., lead author and director of the Ophthalmic Genomics Laboratory at NEI.

The study was funded by the NEI Intramural Research Program.

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