Understanding the mechanics of a rare blinding disorder passed from parents to their children

Researchers at the University of Dundee and Ulster University have discovered that faults in a gene that’s responsible for the structure and stability of cells in the clear front surface of the eye (the cornea) lead to protein misfolding and cell death. The same process is active in Alzheimer’s, cystic fibrosis other eye disorders such as retinitis pigmentosa.

The research was funded in the UK by Fight for Sight, Wellcome Trust and the Medical Research Council.

Severe Meesmann can blind

Meesmann epithelial corneal dystrophy is a rare inherited condition in which very small cysts (microcysts) form in the outer layer (epithelium) of the cornea. Symptoms include being sensitive to light (photophobia), blurred vision, feeling like there’s a foreign-body in the eye and burst cysts. In the most severe form of Meesmann the centre of the cornea becomes scarred and cloudy. This can lead to blindness.

We know from previous research that 23 faults in the gene known as KRT12 and three in the gene KRT3 cause some degree of Meesmann. These genes make the keratin proteins called K12 and K3 which are only found in the cornea. They bind together to form the internal scaffolding of cells in the cornea’s outer layer.

K12 mice  

 
In this study, the research team was trying to understand how faulty K12 leads to microcysts forming and bursting. To do so, they worked with mice that have the same genetic fault (called K12-Leu132Pro) that causes the most severe form of Meesmann in humans.

The team looked at how keratin was distributed in the cornea and at corneal structure in the K12 mice. They compared the result to human corneal tissue samples.

Results showed that the outer layer of the cornea in K12 mice was 50 percent thicker than it is in normal mice. Cells in the K12 mice had a disorganised structure and showed signs of being frail.

The K12 mice also had changes to the pattern of gene and protein activity in the cornea. Some keratin genes were either more or less active than normal, and a protein called CHOP was more active than normal. CHOP is involved in cleaning-up misfolded protein debris from cells.

A similar pattern of changes was seen in the human tissue samples from a patient with the same K12 fault, compared to tissue from a healthy human cornea.

Dr Dolores M Conroy, Director of Research at Fight for Sight, said:

“The top priority for corneal research identified by the Sight Loss and Vision Priority Setting partnership was to answer the question of whether gene or stem cell therapies can be developed. Identifying the means by which a genetic fault causes harm is a vital step on that path. The humanised mouse model of Meesmann developed in this study will be invaluable for further understanding of the disease mechanisms and for the testing of new therapies that could prevent protein misfolding, or gene editing to correct the genetic fault.”

The study is published in the journal Human Molecular Genetics with results from Fight for Sight projects led by Professor Irwin McLean, Professor of Human Genetics in the College of Life Sciences at the University of Dundee and Professor Tara Moore, group leader for vision science research in the School of Biomedical Science at Ulster University.

 Read the full press release.