NIH researchers discover new genetic eye disease


Genetic and clinical research reveals new type of macular dystrophy, a cause of central vision loss.

Retinal images of a patient with a TIMP3 mutation causing atypical symptoms. While there is visible damage in the retina (dark circles), there is no CNV present. (Image courtesy of NEI)

Retinal images of a patient with a TIMP3 mutation causing atypical symptoms. While there is visible damage in the retina (dark circles), there is no CNV present. (Image courtesy of NEI)

A new disease that affects the macula has been identified by a team of researchers from the National Eye Institute (NEI).

According to a National Institutes of Health news release, scientists have reported their findings on the novel macular dystrophy, which is yet to be named, in JAMA Ophthalmology.1 NEI is part of the National Institutes of Health.

The NIH news release noted that macular dystrophies are disorders that usually cause central visual loss because of mutations in several genes, including ABCA4BEST1PRPH2, and TIMP3.

For example, patients with Sorsby Fundus Dystrophy, a genetic eye disease specifically linked to TIMP3 variants, usually develop symptoms in adulthood. They often have 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 from the retinal pigment epithelium (RPE), a layer of tissue that nourishes and supports the retina’s light-sensing photoreceptors. All TIMP3 gene mutations reported are in the mature protein after it has been “cut” from RPE cells in a process called cleavage.

Bin Guan, PhD, the study’s lead author, pointed out that investigators 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,” Guan explained in the news release.

Moreover, the findings by the investigators were followed with clinical evaluations and genetic testing of family members to verify that the two new TIMP3 variants are connected to this atypical maculopathy.

“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 neovascularization, unlike typical Sorsby Fundus Dystrophy,” said Cathy Cukras, MD, PhD, a Lasker tenure-track investigator and medical retina specialist who clinically evaluated the patients.

According to the news release, 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, including Sorsby Fundus Dystrophy.

“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,” Rob Hufnagel, MD, PhD, senior author and director of the Ophthalmic Genomics Laboratory at NEI, said in the news release.

The study was funded by the NEI Intramural Research Program.


Bin Guan, PhD, Laryssa A. Huryn, MD, Andrew B. Hughes, BS, Zhiyu Li, MD, Chelsea Bender, BS, Delphine Blain, MS, MBA, Amy Turriff, MS, Cathy A. Cukras, MD, PhD, Robert B. Hufnagel, MD, PhD. Early-onset TIMP3-related retinopathy associated with impaired signal peptide. JAMA Ophthal. doi:10.1001/jamaophthalmol.2022.1822

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