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NIH researchers discover new genetic eye disease

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

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.

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

Macular dystrophies are disorders that typically cause loss of central vision 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, usually 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 TIMP3 the reported 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 that the gene uses to “cut” the protein from cells. We showed that these variants prevent cleavage, causing the protein to block within the cell, likely leading to retinal pigment epithelial toxicity,” said Bin Guan, Ph.D., lead author.

The research team followed up these results 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.

The NEI Ophthalmic Genomics Laboratory collects and manages samples and diagnostic data from patients who have been recruited into multiple studies within the NEI clinical program to facilitate research into rare eye diseases, including dystrophy of the Sorsby background.

“Discovering new pathological mechanisms, even in known genes like TIMP3can help patients who have been searching for the right diagnosis and hopefully lead to new therapies for them,” said Rob Hufnagel, MD, Ph.D., lead author and director of NEI’s Ophthalmic Genomics Laboratory.

The study was funded by the NEI Intramural Research Program.

NEI leads federal government research on the visual system and eye disease. NEI supports basic and clinical science programs to develop sight-saving treatments and address the special needs of people with vision loss. For more information, visit

About the National Institutes of Health (NIH): The NIH, the country’s medical research agency, comprises 27 institutes and centers and is part of the US Department of Health and Human Services. The NIH is the primary federal agency that conducts and supports basic, clinical, and translational medical research, and studies the causes, treatments, and cures for common and rare diseases. For more information about the NIH and its programs, visit

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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 TIMP3-related retinopathy associated with an altered signal peptide. doi:10.1001/jamaophthalmol.2022.1822

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