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Genetic and clinical research reveals new type of macular dystrophy, a cause of central vision loss
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June 8, 2022
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<a href="/about/news-and-events/news?initiatives=225" hreflang="en">Medical Genetics and Ophthalmic Genomics Unit</a>
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<img src="https://www.nei.nih.gov/sites/default/files/styles/small/public/2022-06/TIMP3%20retinopathy_1.png?itok=6bBDR8_R" alt="Two images, red and black, showing dark circles indicative of eye disease" width="348" height="395">
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<p>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 choroidal neovascularization present.</p>
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<p>Credit: National Eye Institute.</p>
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<p>Researchers from the National Eye Institute (NEI) have identified a new disease that affects the macula, a small part of the light-sensing retina needed for sharp, central vision. Scientists report their findings on the novel macular dystrophy, which is yet to be named, in JAMA Ophthalmology. NEI is part of the National Institutes of Health.</p><p>Macular dystrophies are disorders that usually cause central visual loss because of mutations in several genes, including <em>ABCA4</em>, <em>BEST1</em>, <em>PRPH2,</em> and <em>TIMP3</em>.</p><p>For example, patients with Sorsby Fundus Dystrophy, a genetic eye disease specifically linked to <em>TIMP3</em> 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.</p><p>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 <em>TIMP3 </em>gene mutations reported are in the mature protein after it has been “cut” from RPE cells in a process called cleavage.</p><p>“We found it surprising that two patients had <em>TIMP3</em> 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, Ph.D., lead author.</p><p>The research team followed these findings with clinical evaluations and genetic testing of family members to verify that the two new <em>TIMP3</em> variants are connected to this atypical maculopathy.</p><p>“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, M.D., Ph.D., a Lasker tenure-track investigator and medical retina specialist who clinically evaluated the patients.</p><p>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.</p><p>“Discovering novel disease mechanisms, even in known genes like <em>TIMP3</em>, may help patients that have been looking for the correct diagnosis, and will hopefully lead to new therapies for them,” said Rob Hufnagel, M.D., Ph.D., senior author and director of the Ophthalmic Genomics Laboratory at NEI.</p><p>The study was funded by the NEI Intramural Research Program.</p><p><strong>References:</strong></p><p>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. <a href="https://jamanetwork.com/journals/jamaophthalmology/fullarticle/10.1001/jamaophthalmol.2022.1822?guestAccessKey=61382fd2-cb5b-4569-88ef-d74dd28e471c&utm_source=For_The_Media&utm_medium=referral&utm_campaign=ftm_links&utm_content=tfl&utm_term=060922">doi:10.1001/jamaophthalmol.2022.1822</a></p><p>###</p><p>NEI leads the federal government’s research on the visual system and eye diseases. NEI supports basic and clinical science programs to develop sight-saving treatments and address special needs of people with vision loss. For more information, visit <a href="/">https://www.nei.nih.gov</a>.</p><p>About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit <a href="https://www.nih.gov/">https://www.nih.gov/</a>.</p><p>NIH…Turning Discovery Into Health®</p>
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