EFEMP1 p.Arg140Trp Variant Identified as Cause of Newly Recognized Late-Onset Retinal Degeneration
核心洞察
An international research team identified the EFEMP1 (搜索) p.Arg140Trp variant as the cause of a previously unrecognized inherited retinal degeneration (搜索) affecting peripheral and night vision.
The newly described condition, provisionally termed EFEMP1-associated late-onset retinal degeneration (搜索) (L-ORD), was found in three unrelated families across multiple countries.
Rod photoreceptor dysfunction can be detected before visible structural retinal damage, providing a functional marker at a stage when photoreceptor cells remain intact.
An international research team has identified a previously unrecognized form of inherited retinal degeneration (搜索) caused by a specific variant in the EFEMP1 (搜索) gene, according to results published in JAMA Ophthalmology. The disorder, which the researchers are referring to as EFEMP1-associated late-onset retinal degeneration (搜索) (L-ORD), primarily affects the peripheral retina and the rod photoreceptors responsible for vision in dim light and darkness.
The work was led by the University Hospital and University of Bonn, together with the universities of Edinburgh, Basel and Pennsylvania, with additional contributions from Charles University (搜索) in Prague. Researchers studied three unrelated families carrying the same rare EFEMP1 (搜索) variant, p.Arg140Trp, working across centers in Edinburgh, Basel, Philadelphia, Prague and Bonn.
"What made this discovery possible was bringing together observations that, in isolation, could easily have been interpreted as coincidental genetic variation," said co-first author Chloe M. Stanton of the University of Edinburgh, who led the study with co-first author Georg Ansari of the University of Basel. "By combining genetic information across families with detailed clinical and experimental data, we were able to connect them to a single genetic cause and define a disease phenotype that had not previously been recognized as such."
One Gene, Two Distinct Retinal Diseases
The findings establish p.Arg140Trp as the cause of a distinct, late-onset retinal degeneration that differs markedly from other diseases previously associated with EFEMP1 (搜索). The already-known EFEMP1-related condition, linked to the p.Arg345Trp variant, affects the macula and causes loss of central vision first. By contrast, the newly described disease begins in the periphery of the retina and impairs peripheral and night vision.
The investigation began with a clinical description of a United States family in 1998 and expanded to multiple European families as new genetic information emerged. According to Artur V. Cideciyan, PhD, of the Scheie Eye Institute at the Perelman School of Medicine at the University of Pennsylvania, the family's different disease expression was initially thought to resemble a condition caused by C1QTNF5 (搜索) gene variants, but none of the variants associated with that disease were found. Collaborators then identified the new variant in EFEMP1 (搜索), a gene that normally causes a disease in which the macula is affected first.
Functional Loss Precedes Visible Structural Damage
The newly described disorder follows a distinctive pattern. Disease manifestations predominantly involve the peripheral retina, while the central retina — including the area responsible for high-resolution vision — can remain relatively well preserved for many years. Early symptoms include difficulty seeing at dusk or in darkness and progressive loss of peripheral visual function. Because visual acuity may initially remain completely normal and routine retinal examination can appear unremarkable, the disease may go undetected for a considerable period.
In several patients carrying the variant, researchers found markedly delayed recovery of rod-mediated vision after exposure to light, despite normal visual acuity and an apparently normal retina. "One of the most striking findings is that retinal dysfunction clearly precedes visible structural degeneration," said co-corresponding author Cideciyan. "We can detect a major abnormality in the way rod photoreceptors recover in darkness at retinal locations that still look structurally intact. This gives us a functional marker of disease at a stage when photoreceptor cells have not yet been lost."
Laboratory experiments provided clues as to why the variant is pathogenic. The p.Arg140Trp form of the EFEMP1 (搜索) protein accumulated unusually inside cells, showed an increased tendency to form abnormal molecular complexes, and was less efficiently secreted from cells. The condition also causes abnormally thick material to build up between the eye's cells.
Prevalence Unknown, Broader Implications for Retinal Aging
The researchers are currently unsure how widespread the variant is and, consequently, how many people may have this form of L-ORD. Although they believe it may be relatively rare, larger studies will be required to determine its frequency.
The team suggests the discovery could inform understanding of age-related sight conditions more broadly. "Aging is a risk factor for many medical conditions, including retinal diseases such as age-related macular degeneration (搜索), the most common retinal condition of aging," said Tomas S. Aleman, MD, a professor of Ophthalmology and co-director of the Center for Hereditary Retinal Degenerations at Penn. "Lessons learned from these infrequent, late-onset genetic eye diseases offer glimpses at possible mechanisms of disease for much more frequent retinal problems."
The study was supported by grants from the University of Edinburgh Chancellor's Fellowship award, the RS Macdonald Charitable Trust Seedcorn Award, the BrightFocus Foundation (M2024009N), the German Research Foundation (532367710), the Medical Research Council (MC_UU_00035/9, MC_UU_00007/10), the Swiss National Science Foundation (204285), the Ministry of Health of the Czech Republic (NW24-06-00083), Charles University (搜索) in Prague (UNCE/24/MED/022 and SVV 2600631), and the Samuel G. Jacobson, MD, PhD, Memorial Fund.