Errors in ‘proofreading’ cause inherited blindness

Errors in 'proofreading' cause inherited blindness
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Mistakes in ‘proofreading’ the genetic code of retinal cells is the cause of a form of inherited blindness produced by mutations in splicing factors.

A new understanding of the disease process, published in Nature Communications, is leading to the development of a gene therapy for retinitis pigmentosa (RP), a form of inherited blindness, caused by splicing factor defects.

Inherited blindness and splicing factors

The research, led by Professor Majlinda Lako at Newcastle University, UK, investigated how a common form of inherited blindness, retinitis pigmentosa, is caused by genetic defects in splicing factors.

Splicing factors are important protein components of the gene proofreading or ‘splicing’ mechanism that is found in all cells.

Elements of DNA, known as introns, are spliced out or removed by the cell during protein construction, in order for the final intelligible genetic code to remain. This is because the introns do not actually provide any meaningful instructions for making proteins. Variations in splicing can cause very different consequences on the formation or function of cells, including retinal cells.

Defects in splicing factors

Stem cells derived from skin samples were used to create a ‘retina in a dish’, the scientists sourced skin samples donated by retinitis pigmentosa patients at the University of Leeds, UK.

The researchers have shown that defects in splicing factors cause defective proofreading of components of the editing machinery itself. This implausible effect resulted in a ‘vicious cycle’ of disruptive misinterpretation of the genetic code.

The formation and functions of a special type of retinal cells, retinal pigment epithelial (RPE) cells, are the most severely affected. These cells are critical for supporting and nourishing photoreceptors, so when an issue occurs, the light-processing function of the retina breaks down, resulting in sight loss.

For the first time, this study shows how genetic defects in splicing factors cause variations in the proofreading of retinal genes, leading to imperfections in retinal cell function and their eventual degeneration in retinitis pigmentosa.

Is there hope for clinical trials?

With the study being the first of its kind to make sense of how diseases such as inherited blindness develops, the researchers hope for clinical trials to commence within 5 years.
Lako said: “This research gives us much deeper and broader insights into how splicing factors cause retinitis pigmentosa, enabling the next step in our research – the design of gene therapies for future treatments.”

Nevertheless, there is still much to learn about why splicing factors are so necessary for the retina to function and how scientists might repair or treat this in individuals with this type of RP. However, this work will focus research on the right models and pathways for future development.

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