Discovery of a new genetic eye disease – Neuroscience News

Summary: Researchers have identified a new genetic eye disease that affects the macula.

Source: NIH

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 protein to block within the cell, likely leading to retinal pigment epithelial toxicity,” said Bin Guan, Ph.D., lead author.

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

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.

Funding: The study was funded by the NEI Intramural Research Program.

About this genetics and vision research news

Author: Claudia Costabile
Source: NIH
Contact: Claudia Costabile – NIH
Image: Image is in public domain

Original research: Access closed.
“Timp3-related early retinopathy associated with an altered signal peptide” by Bin Guan et al. JAMA Ophthalmology


Early TIMP3-related retinopathy associated with an altered signal peptide


Sorsby’s fundus dystrophy is a typical adult maculopathy with a high risk of choroidal neovascularization. Sorsby’s fundus dystrophy, inherited as an autosomal dominant fully penetrant trait, is associated with TIMP3 variants that cause protein aggregation in the extracellular matrix.


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Assess the phenotype and underlying biochemical mechanism of the disease TIMP3 variants modifying the NOT-terminal signal peptide in 2 families with early diffuse maculopathy without choroidal neovascularization with cosegregation of TIMP3 variants in the signal peptide sequence.

Design, framework and participants

This case series of 2 families with early diffuse maculopathy was performed at the National Eye Institute, National Institutes of Health Clinical Center. Data was collected and analyzed from October 2009 to December 2021.

Main results and measures

Clinical imaging and molecular genetic testing were performed in 2 families with macular dystrophy. Cosegregation analysis of TIMP3 variants was performed in affected and unaffected family members. Candidate TIMP3 signal peptide variants were evaluated for cleavage defects after transfection.


Eleven individuals from 2 families with early diffuse maculopathy without harboring choroidal neovascularization TIMP3 variants (L10H or G12R) in the NOT-terminal signaling peptide were analyzed. Co-segregation with the phenotype was confirmed in other family members. Biochemical analysis confirmed defects in protein maturation and extracellular deposition.

Conclusions and relevance

This study revealed that TIMP3 the function-impairing variants of the signal peptide deviated from classic Sorsby fundus dystrophy in both phenotypic features and underlying mechanism. These results suggest that the atypical patient presentations are caused by defects in the signal peptide TIMP3, associated with impaired cleavage and deposition in the extracellular matrix, implying a new disease of macular dystrophy.

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