Working across centers in Edinburgh, Basel, Philadelphia, Prague and Bonn, the researchers studied three unrelated families carrying the same rare EFEMP1 variant, p.Arg140Trp. Their findings establish this variant as the cause of a distinct, late-onset retinal degeneration that differs markedly from other diseases previously associated with EFEMP1.
“What made this discovery possible was bringing together observations that, in isolation, could easily have been interpreted as coincidental genetic variation. 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,” says co-first author Chloe M. Stanton from the University of Edinburgh, who led the study together with co-first author Georg Ansari from the University of Basel. Laboratory experiments provided further clues as to why. The p.Arg140Trp form of the EFEMP1 protein accumulated unusually inside cells, showed an increased tendency to form abnormal molecular complexes, and was less efficiently secreted from cells.
Disease can begin before retinal damage is visible
The newly described disorder follows a distinctive pattern. Disease manifestations predominantly involve the responsible for perceiving the surroundings peripheral retina, which is responsible for perceiving the surroundings, 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 examination of the retina 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,” says co-corresponding author Artur V. Cideciyan from the University of Pennsylvania. “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.”
One gene, two strikingly different retinal diseases
EFEMP1 was already known to cause Doyne honeycomb retinal dystrophy/Malattia Leventinese, a rare inherited retinal condition historically associated with the Leventina Valley in Switzerland. However, the established form of Malattia Leventinese is caused by a different EFEMP1 variant, p.Arg345Trp, and primarily affects the central retina. The newly characterized p.Arg140Trp variant affects the peripheral retina, while the macula – the central retinal region responsible for high-resolution vision – remains relatively preserved. The study therefore demonstrates that different variants within the same gene can result in strikingly different patterns of retinal disease.
“Previously, EFEMP1 was strongly associated with a very characteristic central retinal phenotype. We now show that another variant in the same gene can produce a fundamentally different disease, with essentially an opposite disease pattern,” says co-corresponding author Maximilian Pfau from the UKB, who also conducts research at the University of Bonn. “The newly described disease shares similarities with other rare inherited eye disorders including gyrate atrophy, choroideremia, extensive macular atrophy with pseudodrusen, and diffuse-trickling geographic atrophy, particularly at advanced stages. EFEMP1 p.Arg140Trp-related disease may therefore account for eye disorders whose underlying genetic cause has so far remained unresolved.”
The researchers caution that the present study includes only three unrelated families. Larger studies will be needed to determine the full clinical spectrum, natural history and frequency of the newly defined condition, and to assess potential therapeutic strategies.