Towards the elucidation of hereditary retinal diseases of unknown cause

One of the most common causes of hereditary vision loss is retinitis pigmentosa, a genetic disorder in which the molecular mechanisms involved are poorly understood. Between 40 and 50 percent of cases of retinitis pigmentosa are unexplained, which means that those affected carry mutations in genes yet to be identified.

Retinal cells are some of the most complex and specialized cells in the human body. Recent research reveals the mechanisms that make this specialization possible. Because of this complexity, retinal cells depend on many unique genes for their development, any one of which can have a disease-causing mutation that results in vision loss.

The authors of the study, from the Center for Genomic Regulation (CRG), in Barcelona, ​​have found that the Srrm3 gene is a crucial master regulatory gene for the development of photoreceptors, cells at the back of the retina that capture and process light, sending signals to the brain that activate vision. Deletion of this gene in zebrafish during an experiment resulted in severe visual impairment.

The international research team found that in vertebrates, Srrm3 regulates alternative splicing, a process that allows cells to make more than one type of protein from a single gene. Alternative splicing activity is particularly prominent in neuronal cells, and its misregulation can have a devastating impact on human health, for example by promoting cancer or neurological disorders.

The study authors found that Srrm3 specifically regulates the splicing of microexons, small pieces of DNA that are only 3 to 27 genetic code letters long. Despite their small size, regulation of microexons has been shown to play a critical role in protein and cellular function.

Zebrafish retinal cells with the segment of photoreceptor cells responsible for transforming light into nerve signals stained green. This segment is significantly degraded in Srrm3 knockout retinal cells (right) compared to normal retinal cells (left). (Images: Ludovica Ciampi/CRG. CC BY-ND)

The team was able to identify dozens of different microexons in photoreceptors, but not in other neurons. The vast majority of these microexons affect the function of some 70 genes important for the development of the outer segment of a photoreceptor, the part of the cell that absorbs light.

The study authors plan to conduct follow-up studies to assess whether Srrm3 or the microexons involved could explain some of the cases of retinitis pigmentosa with no known cause.

“Until now, the Srrm3 gene has not been associated with the development of photoreceptor cells or with the pathogenesis of retinal diseases. We are already exploring the role of the gene in patients without a genetic diagnosis. If we find cases with mutations in this specific gene, or in any microexon of the retina, this could lead us to possible new therapeutic strategies to control the condition”, says Ludovica Ciampi, doctoral student at the CRG and first author of the study.

According to ICREA research professor Manuel Irimia, understanding how microexons are regulated in different cell types will be key to identifying new therapeutic targets. “Photoreceptors have unique properties thanks to the regulation of alternative splicing and microexons. This helps make the cell more specialized but also perhaps more susceptible to genetic disease. It is now possible to modulate splicing activity, so the more we know about this complex biology, the more likely it is that we will find therapeutic targets to treat retinal diseases”, concludes Dr. Irimia.

The study is titled “Specialization of the photoreceptor transcriptome by Srrm3-dependent microexons is required for outer segment maintenance and vision.” And it has been published in the academic journal Proceedings of the National Academy of Sciences (PNAS). (Source: CRG)