Albinism
'Not so Black and White'
Albinism is an inherited genetic disorder characterized by lack of melanin pigment in the eyes, skin, and hair. It carries the risk of lifelong vision impairment, as well as higher susceptibility to skin cancer. 22 genes have been identified so far that are linked to albinism. Could there be some kind of functional connection?
Connecting clinical and research data
Prof. Arthur Bergen, head of Section Ophthalmogenetics, and his group focus on the development of innovative pre-clinical research in genetic eye disease. The key highlight of their latest study and extensive review entitled “The retinal pigmentation pathway in human albinism: Not so black and white” is the proposal of a single functional genetic pigmentation pathway involving all 22 genes related to neurodevelopmental and metabolic functions in the retina.
“It is complex! All genes linked to albinism seem to have a different function and clinical phenotypes are diverse.” Prof. Arthur Bergen, section head and Professor in Ophthalmogenetics at Amsterdam UMC.
“We had to connect the clinical, genetic, and cellular data to see the big picture,” says Prof. Bergen “In the end, we were able to link all the known genes associated with albinism. Not just the genes, also their functions and corresponding cellular defects.”
Link to disease pathology
Defects in genes that function earlier in the proposed pathway result in a broader and more severe clinical phenotypes than mutations in genes that act downstream in more specific ways. “Upstream actors, like those responsible for the genesis or function of cellular organelles like melanosomes, cause syndromic forms of albinism,” explains Prof. Bergen. “And more specific defects cause increasingly restricted phenotypes.”
A framework for future research
The conceptualization of a single functional retinal pigmentation pathway opens up many new avenues of future research. One new technological possibility is advanced in vitro modelling of albinism using stem cell-derived (mutant) retinal pigment epithelial (RPE) cell cultures and retinal organoids: lab grown three-dimensional (3D) mini retinal structures.
“In fact, in 2022, using the CRISPR-Cas gene editing system, my team was successful in cultivating retinal organoids that lacked the melanin pigment. These ‘albino’ organoids can be used to test therapies and study biological processes in mutant retinal structures,” says Prof. Bergen.
Other possible lines of inquiry include further clinical (sub-)classification in relation to genotype, the role of specific signaling molecules in the proposed pathway, and the function of exosome signaling in the developing retina.
Prof. Bergen: “This provides not only a framework for future research, but also indicates there may be new therapeutic options to explore, for example, gene therapy or targeted drugs affecting the regulation and activity of the retinal pigmentation pathway. Therefore, albinism has been selected as one of six key diseases for further translational research by the Emma Center for Personalized Medicine.”
Beyond the pale
In addition to albinism, the researchers suggest that the proposed retinal pigmentation pathway could play a role in other retinal pathologies. One example was the photoprotective role of specific retinal pigments that are thought to play a part in age-related macular degeneration (AMD).
“We know macular pigments decline with age,” says Prof. Bergen. “But the role of melanosomal pigments in AMD is not well understood. Does albinism or reduced pigmentation have a less protective effect, or is there an indirect effect due to altered signaling through the proposed retinal pigmentation pathway?”
Given his team’s recent success in reaching a proof-of-principle phase with their first 3-D bio-printed retinal model for macular degeneration, perhaps some of these questions can be answered.
“One thing is for sure. Research such as this provides valuable insights, but it also opens so many different avenues for further inquiries. To young researchers out there, I would tell them focus is important. If we are all just able to find one cure for one disease in a lifetime, the world will be very different in 30 years.”
“If we are all just able to find one cure for one disease in a lifetime, the world will be very different in 30 years.” Prof. Arthur Bergen
For more information, read the publication or watch this interview with Prof. Arthur Bergen.
Bakker, R., et al. (2022) The retinal pigmentation pathway in human albinism: Not so black and white. Prog Retin Eye Res 91, 101091. https://doi.org/10.1016/j.preteyeres.2022.101091.
More information and news from the Section Ophthalmogenetics is now available on their recently launched website: Ophthalmogenetics.nl.
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