Breakthrough discovery in the genetics of corneal dystrophies

Researchers at the UCL Institute of Ophthalmology and Moorfields Eye Hospital London, in collaboration with colleagues in the Czech Republic, have discovered a new genetic cause of corneal dystrophy.

Corneal dystrophy is a group of inherited disorders that affect the transparency of the cornea and can lead to severe sight loss or blindness. The only currently available treatment for most individuals who are severely affected is corneal replacement by a transplant.

For two types of dominantly inherited corneal endothelial dystrophy, congenital hereditary corneal dystrophy (CHED1) and posterior polymorphous corneal dystrophy (PPCD1) the genetic basis has remained unknown until now.

In a landmark paper, published in the international journal American Journal of Human Genetics, researchers describe alterations in the DNA sequence that affects regulation of a gene called OVOL2 in over 100 individuals with CHED1 and PPCD1. The more severely affected individuals have symptoms at birth, with corneal haze evident as early as 1 year of age. These individuals almost always require corneal transplantation surgery.

The research team was led by Professor Alison Hardcastle and Mr Stephen Tuft at UCL Institute of Ophthalmology and Moorfields Eye Hospital and the associated National Institute for Health Research (NIHR) Biomedical Research Centre (BRC). They used new technological advances in sequencing the human genome to discover the genetic cause.

Professor Hardcastle said: "It was a challenge to identify the DNA alterations causing these conditions because they influence how the OVOL2 gene is regulated, rather than affecting the 'coding' sequence of the gene like most other changes in previously identified genes implicated in eye conditions."

Dr Dolores M Conroy, Director of Research at Fight for Sight, said: "This study is not only important for understanding the cornea in health and disease, but also represents an important major advance in the field of human genetics, enhancing understanding of the 'non-coding' regions of the human genome that dictate where, and when, a gene should be switched on or off."

Mr Frank Larkin, Director of the NIHR Moorfields Clinical Research Facility for Experimental Medicine, said, "This study marks a significant step along the translational pathway. By confirming the origin of genetic corneal dystrophy, the group has paved the way for targeted research that could ultimately result in better therapies for patients."

Fight for Sight PhD student Cerys Evans is joint first author of the study and is a working on dominantly inherited corneal dystrophies. Dr Alice Davidson is joint first author and was supported by funding from the Lanvern Foundation, Moorfields Eye Charity and Moorfields Special Trustees. Dr Petra Liskova trained at UCL Institute of Ophthalmology and Moorfields Eye Hospital and led the research in the Czech Republic. Dr Alice Davidson is now a Fight for Sight funded Early Career Investigator.

Their discovery paves the way for further studies to understand the biological processes leading to corneal dystrophy and to develop new treatments, with the future hope of replacing the need for corneal transplants in this group of patients.