The molecular map of congenital stationary night blindness – the science of seeing in the dark
A recently published study has provided the first molecular map of the mutation-specific changes that occur in the retina which lead to Congenital Stationary Night Blindness.
What is congenital stationary night blindness?
Congenital Stationary Night Blindness (CSNB) is an inherited retinal condition that affects a person’s ability to see in low light and darkness. The condition is present at birth, however unlike most inherited retinal diseases (IRDs) that progress over time, CSNB remains stable. Individuals with CSNB usually have normal or near-normal vision in bright light. At present, there is no cure for CSNB and individuals are encouraged to maximise their vision by using low vision aids, using brighter lights at home and work and avoiding activities that require good night vision such as driving in the dark.
What causes it?
CSNB is caused by mutations in the genes that affect a calcium channel (CaV1.4) in the retina, which is essential for sending light signals from the photoreceptors in the eye through the neurons to the brain. Currently, at least 17 different genes have been identified as causing CSNB, and whilst ophthalmologists can diagnose the condition by using both genetic tests and eye tests, they can’t explain how a specific mutation in a gene affects cell function.
This new study by researchers at the University of Innsbruck in Austria shows that each mutation changes the retina in a slightly different way which leads to CSNB. This is a remarkable step forward in CSNB research as it could mean that future treatments can be developed and tailored to the specific mutation an individual has rather than using a one-size-fits-all approach.
The study:
The research team led by Matthias Ganglberger and Alexandra Koschak at the University of Innsbruck carried out a proteomic study, which refers to the large-scale analysis of proteins. They used mouse models with two different versions of the CSNB causing mutation, RX and IT, and compared these with a healthy mouse model to show how the proteins in the retina changed causing the calcium channel to work incorrectly.
The study found that although both models exhibited signs of retinal stress, cell damage and inflammation, different mutations caused different molecular changes. The RX mutation mainly disrupted proteins involved in synaptic organisation and function, whereas the IT mutation mainly disrupted proteins involved in metabolic pathways. This is particularly interesting as the RX and IT variants result from mutations in the same gene and despite this cause vastly different molecular consequences.
“Interestingly, these two mutations exhibit partially opposing biophysical properties. They differ in their gating behaviour, that is, how the channel opens and closes, which in turn alters calcium influx into the synapse.” – Alexandra Koschak, Department of Pharmacology and Toxicology at the Institute of Pharmacy, University of Innsbruck
This suggests that CSNB as a condition comprises of different subtypes depending on how a mutation affects the calcium channel. This has huge implications on the diagnosis process and treatment development for CSNB, as it suggests that identifying the causative mutated gene is insufficient. Understanding how a specific mutation causes the channel malfunction is essential for understanding the molecular consequences of the disease.
“The finding that different mutations give rise to distinct molecular profiles is a decisive step toward the development of targeted, personalized therapies.” – Alexandra Koschak, Department of Pharmacology and Toxicology at the Institute of Pharmacy, University of Innsbruck
Next steps:
It is important to note that although this work has shown promising results in animal models, it is still at an early preclinical stage. The research team at Innsbruck now plan to conduct follow-up studies to validate these results and investigate whether these findings can be translated to the human population in the future.