Misfolding protein causes familial, blinding cornea condition

New research points finger as misfolded keratin as cause of rare Meesmann epithelial corneal dystrophy


Parents are passing down genetic instructions for a misfunctioning protein to their children in inherited Meesmann epithelial corneal dystrophy (MECD), new UK research concludes.

MECD causes microcysts to form in the corneal epithelium. Symptoms include cyst rupture, photophobia, blurred vision and foreign-body sensation. In severe cases, the cornea is scarred, and the resulting corneal clouding can cause blindness.

Researcher and Ulster University professor, Dr Tara Moore, told OT that the genes for the protein keratin’s K12 and K3 varieties, which bind together in the cornea, have already been associated with MECD.

She said these keratin proteins are the: “same as in skin cells, hold[ing] together the infrastructure of your cells.”

However, the exact reason for the symptoms seen in the inherited condition was not known until Dr Moore and her Ulster colleagues launched a research project, with the University of Dundee and Danish scientists, to look at the K12 gene.

Mice were genetically engineered with two sets of a faulty version of the K12 protein gene, based on the DNA found in humans with the most severe form of MECD, in the research published in the journal Human Molecular Genetics.

The mice developed thicker cornea, with disorganised and fragile cells. Similar to MECD patients, these cells also had raised activity of a protein known as ‘CHOP’, which ‘cleans’ cells of misfolded proteins.

Because long-term activation of CHOP triggers deliberate cell death, Dr Moore and her team suspect that the misfolding of the protein is the cause they were seeking to explain MECD symptoms.

The findings also showed the eyes of MECD patients were “highly susceptible to cellular stress,” she added.

Dr Moore said the findings pave the way for a genetic therapy. Her lab is currently working on two options – the first using small interfering RNA [siRNA] administered in a daily eye drop to correct the misfolding keratin in appropriate patients.

The second utilised ‘CRISPR’ gene-editing, which could be a one-off cure, she explained. Her Ulster lab was the first in the world to successfully demonstrate the revolutionary faulty gene-cutting technology in an animal.

Dr Moore said the two alternatives could, one day, work side by side. She explained: “It would be someone’s personal choice. The siRNA drops are slightly safer and are temporary – you could stop using the drops the next day – [but] they might think: ‘I don’t want to do siRNA drops for the rest of my life.’”

Dr Moore said, while some genetic mutations classified as MECD had a significant impact, others had minor effects. She noted optometrists or ophthalmologists might not be able to spot every case: “The patient may not even be aware. Some cases are relatively benign, depending on the mutation.”

Treatment was also beginning to take these personal differing mutations into account, for example pre-screening patients for the related Avellino corneal dystrophy before they underwent laser refractive surgery. The procedure can exacerbate the condition, Dr Moore noted.

The research was funded by Fight for Sight, the Wellcome Trust and the Medical Research Council, and released for Rare Disease Day (29 February).