A new genetic disease of the eye has been discovered

Summary: Scientists have identified a new genetic eye disease that affects malaria.

A source: NIH

Researchers at the National Institute of Ophthalmology (NEI) have identified a new disease that affects the cornea, a small part of the light-sensitive retina needed for clear, central vision. Scientists have announced the results of an unnamed new macular dystrophy JAMA Ophthalmology. NEI is part of the National Institutes of Health.

Macular dystrophies are diseases that result in central vision loss, usually due to mutations in several genes, such as ABCA4, BEST1, PRPH2, and TIMP3.

For example, patients with genetic eye disease associated with Sorsby Fundus Dystrophy, TIMP3 variants, usually develop symptoms in adulthood. They often undergo sudden changes in visual acuity due to choroidal neovascularization – new, abnormal blood vessels that grow under the retina, affecting fluid flow and vision.

TIMP3 is a protein that helps regulate blood flow in the retina and is secreted by the retinal pigment epithelium (RPE), which is the supporting tissue layer that nourishes the light-sensitive photoreceptors in the retina. All reported TIMP3 gene mutations occur in a mature protein after it has been “cut” in a process called RPE cell division.

“It was surprising that the TIMP3 variants in both patients were in a short signal sequence that we used to“ cut ”the protein from the gene cells rather than in the mature protein. We have shown these options to prevent division, which leads to the protein getting stuck in the cell, which is likely to lead to toxicity of the retinal pigment epithelium, ”said Bin Guan, Ph.D., lead author.

Macular dystrophies are diseases that result in central vision loss, usually due to mutations in several genes, such as ABCA4, BEST1, PRPH2, and TIMP3. Image in public domain

The research team conducted these findings through clinical evaluation and genetic testing of family members to verify that two new TIMP3 variants were associated with this atypical maculopathy.

“Affected individuals had scotomas, or blind spots, and changes in their macules that were a sign of disease, but so far they have retained central vision and no choroidal neovascularization, unlike typical Sorsby Fundus dystrophy,” said Katie Kukras, MD, Ph.D. .., Lasker’s researcher and retinal medicine specialist who clinically evaluated patients.

NEI’s Ophthalmic Genomics Laboratory collects and manages samples and diagnostic data from patients involved in several studies under the NEI Clinical Program to facilitate the study of rare eye diseases, including Sorsby Fundus Dystrophy.

Rob Hufnagel, MD, Ph.D., senior author, said: “We hope that finding new mechanisms of the disease, even in known genes such as TIMP3, will help patients seeking a correct diagnosis and bring new therapies for them.” Director of the Ophthalmic Genomics Laboratory at NEI.

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

Genetics and visual research news about it

Author: Claudia Costabil
A source: NIH
The connection: Claudia Costabil – NIH
Photo: Image in public domain

Original study: Closed access.
Bin Guan JAMA Ophthalmology


Early-onset TIMP3-associated retinopathy associated with signal peptide impairment

an important

Sorsby bottom dystrophy is a maculopathy that occurs in adults with a high risk of choroidal neovascularization. Sorsby bottom dystrophy, inherited as an autosomal dominant complete transient trait, TIMP3 variants that cause protein aggregation in the extracellular matrix.

The goal

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Assessment of the phenotype and the main biochemical mechanism of the disease TIMP3 options to change Do not– terminal signal peptides in 2 families with early-onset diffusion maculopathy without choreography and choroidal neovascularization TIMP3 variants of the signal peptide sequence.

Design, installation and participants

The series, which consisted of two families with early-onset diffuse maculopathy, was conducted at the National Eye Institute and the National Clinical Health Center. Data were collected and analyzed from October 2009 to December 2021.

Key results and measures

Clinical descriptions and molecular genetic testing were performed in 2 families with macular degeneration. Cosegregation analysis TIMP3 The options were made for affected and unaffected family members. Candidate TIMP3 signal peptide variants were evaluated for clearance defects after transfection.


Eleven people from 2 families, early-onset diffuse maculopathy without choroidal neovascularization port TIMP3 options (L10H or G12R). Do not-term signaling peptide analyzed. Cosegregation by phenotype was further confirmed by family members. Biochemical analysis confirmed defects in protein maturation and extracellular deposition.

Conclusions and relevance

This study revealed TIMP3 Variants that alter the peptide function of the signal deviate from classical Sorsby bottom dystrophy in terms of phenotypic features and underlying mechanism. These results suggest that the patient’s atypical presentations were caused by TIMP3 signaling peptide defects, a new macular degeneration associated with disruption of division and entry into the extracellular matrix.

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