New genetic eye disease discovered

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

Source: NIH

Researchers at the National Eye Institute (NEI) have identified a new disease that affects the macula, a small part of the light-sensitive retina necessary for sharp, central vision. Scientists report their findings on the new macular dystrophy, yet to be named, in JAMA Ophthalmology† NEI is part of the National Institutes of Health.

Macular dystrophies are conditions that commonly cause central vision loss due to mutations in several genes, including ABCA4, BEST1, PRPH2, 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, leak fluid and affect vision.

TIMP3 is a protein that helps regulate blood flow in the retina and is secreted by the retinal pigment epithelium (RPE), a tissue layer that nourishes and supports the retina’s light-sensitive photoreceptors. All of the reported TIMP3 gene mutations reside in the mature protein after it has been “cut” from RPE cells in a process called splicing.

“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 the cells. We have shown that these variants prevent splicing, which causes the protein to become trapped in the cell, likely leading to retinal pigment epithelium toxicity,” said Bin Guan, Ph.D., lead author.

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

The research team followed 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 maculars that indicate disease, but for now they have preserved central vision and no choroidal neovascularization, unlike typical Sorsby Fundus dystrophy,” said Cathy Cukras, MD, Ph. D. ., a Lasker tenure-track researcher and medical retina specialist who clinically evaluated the patients.

NEI’s Ophthalmic Genomics Laboratory collects and manages specimens and diagnostic data from patients recruited into multiple studies within the NEI clinical program to facilitate research into rare eye diseases, including Sorsby Fundus Dystrophy.

“Discovering new disease mechanisms, even in well-known genes such as TIMP3, may help patients seeking the correct diagnosis, and will hopefully lead to new therapies for them,” said Rob Hufnagel, MD, Ph.D., senior author. and director of NEI’s Ophthalmic Genomics Laboratory.

Financing: 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 – NIHO
Image: The image is in the public domain

Original research: Closed access.
“Early-Onset TIMP3-related retinopathy associated with reduced signal peptide” by Bin Guan et al. JAMA Ophthalmology


Early-Onset TIMP3-related retinopathy associated with reduced signal peptide


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


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To evaluate the phenotype and underlying biochemical mechanism of pathogens TIMP3 variants that change the Nterminal signal peptide in 2 families with early diffuse maculopathy without choroidal neovascularization with cosegregation of TIMP3 variants in the signal peptide sequence.

Design, setting and participants

This case series of 2 families with early-onset diffuse maculopathy was conducted 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 relatives. Candidate TIMP3 signal peptide variants were evaluated for splicing defects after transfection.


Eleven subjects from 2 families with early-onset diffuse maculopathy without harbor for choroidal neovascularization TIMP3 variants (L10H or G12R) in the Nterminal signaling peptide were analysed. Cosegregation with phenotype was confirmed in additional relatives. Biochemical analysis confirmed defects in both protein maturation and extracellular deposition.

Conclusions and relevance

This study found that TIMP3 variants altering the function of signal peptides diverged from classical Sorsby fundus dystrophy both in phenotypic features and underlying mechanism. These results suggest that atypical patient presentations are caused by TIMP3 signal peptide defects, associated with impaired cleavage and deposition in the extracellular matrix, indicating a novel macular dystrophy disease.

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