Research & Development

The macula is a small part of the light-sensing retina needed for sharp, central vision. Macular dystrophies cause central visual loss, due to mutations in several genes, including ABCA4, BEST1, PRPH2, and TIMP3.

“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 the cells. We showed these variants prevent cleavage, causing the protein to be stuck in the cell, likely leading to retinal pigment epithelium toxicity,” said Bin Guan, PhD, lead author.

Rob Hufnagel, MD, PhD, senior author and director of the Ophthalmic Genomics Laboratory at NEI, elaborated: “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.”

NEI’s Ophthalmic Genomics Laboratory gathers and manages specimens and diagnostic data from patients who have been recruited into multiple studies within the NEI clinical program, to facilitate research of rare eye diseases. This includes Sorsby Fundus Dystrophy, which causes similar symptoms to agerelated macular degeneration (AMD), though it generally affects patients at a younger age.

“Affected individuals had scotomas, or blind spots, and changes in their maculas indicative of disease, but, for now, they have preserved central vision and no choroidal neovascularisation, unlike typical Sorsby Fundus Dystrophy,” said Cathy Cukras, MD, PhD, a Lasker tenuretrack investigator and medical retina specialist who clinically evaluated the patients.