Functional and therapeutic approaches to congenital stationary night blindness

Research details

  • Type of funding: PhD Studentship
  • Grant Holder: Professor Graeme Black
  • Institute: University of Manchester
  • Region: North West
  • Start date: October 2018
  • End Date: March 2022
  • Priority: Causes
  • Eye Category: Inherited retinal
X-linked Congenital Stationary Night Blindness (CSNB) is a visual disability that is caused by mutations in a gene called CACNA1F. Within the retina the CACNA1F gene makes a protein called Cav1.4 which sits on the cell surface of retinal cells and acts as a channel to allow calcium (in the form of calcium ions) into the cell.

Proteins have to be folded correctly in order to perform their specific function, which for Cav1.4 is allowing calcium ions to enter the cell. 30-40% of the genetic mutations in CACNA1F result in the substitution of a correct amino acid for an incorrect one. 23 novel substitutions have been identified, however it’s unknown whether these are the cause of CSNB.

Researchers aim to improve the molecular diagnoses for a number of eye conditions by verifying computational modelling predictions of variants of unknown significance in the calcium ion channel Cav1.4. Varients in CACNA1F associated with the loss of Cav1.4 function and protein misfolding will be tested, which may be rescued with chemical chaperones.

An analytical process based upon computer-based modelling (i.e. prediction) of three dimensional protein folding has been able to differentiate between disease-causing and non-disease-causing amino acid substitutions in Cav1.4 in groups of patients. Specific amino acid substitutions will be introduced into the Cav1.4 protein to test the computer modelling predictions.

Genetic mutations in CACNA1F will be classified into four classes: Disease-causing, presumed disease-causing, genetic mutations published in the scientific literature as disease-causing but assessed not to be and not disease-causing.

Some disease causing amino acid substitutions prevent the correct localisation of Cav1.4 to the cell’s surface. Recent work has shown that drugs can improve the ability of cells to send proteins that do not fold correctly to the correct part of the cell Protein folding and localisation can be altered using drugs. Different amino acid substitutions in Cav1.4 to assess the ability of these drugs to improve CaV1.4 function in cells will be investigated.

The validation of the computational analysis tool will result in the development of a clinically valuable diagnostic tool. Also, if drugs can successfully correct the localisation of abnormal Cav1.4 and lessen the impact of disease-causing amino acid changes on its function, this will form the basis of a potentially novel treatment.
Therapeutic potential of new tumour suppressor, PRELP, in retinoblastoma