New Genetic Eye Disease Discovered by NIH Researchers

A new form of macular dystrophy, an eye disease that affects a small part of the light-sensing retina needed for sharp, central vision, has been discovered by a team of researchers for the National Eye Institute (NEI), a part of the National Institutes for Health (NIH). The findings were reported last week in the journal JAMA Ophthalmology.

Macular dystrophies comprise heterogeneous disorders characterized by central visual loss, which are caused by pathogenic variants in several genes including ABCA4, BEST1, PRPH2, TIMP3, and others.

Sorsby fundus dystrophy (SFD), a genetic eye disease specifically linked to TIMP3 variants, usually develop symptoms in adulthood. People with this genetic disease 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.

The researchers noted: “Reported SFD cases typically have an age at onset from the third to fifth decades. Here, half of the affected individuals had onset of symptoms and clinical findings in the second decade, indicating relatively early onset. In addition, SFD typically manifests with choroidal neovascularization. However, none of the six affected individuals with detailed ophthalmic records have evidence of choroidal neovascularization, including five individuals older than 50 years with long-standing diagnoses of 20 or more years.”

The new, as-yet unnamed variant of this disease shows activity of TIMP3 that have not before been observed or reported. Previous studies have shown that the TIMP3 protein 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 TIMP3 gene mutations reported are 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 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.

After these new findings, the investigators conducted clinical evaluations and genetic testing 11 individual from two different families with early-onset diffuse maculopathy without choroidal neovascularization harbor TIMP3 variants (L10H or G12R) in the N-terminal signaling peptide. These evaluations revealed cosegregation with phenotype in the additional family members and biochemical analysis confirmed defects in both protein maturation and extracellular deposition of those with the new disease.

To date, the individuals identified with this new disease are exhibiting symptoms similar to Sorsby fundus dystrophy.

“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., director of the Medical Retina Fellowship Program at NEI and a medical retina specialist who clinically evaluated the patients.

Further studies are needed to characterize the spectrum of TIMP3 signal peptide sequence variants, are warranted, the researcher noted, to further validate their findings, and provide new hope to patients with this condition.

“Discovering novel disease mechanisms, even in known genes like TIMP3, 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.