Breakthrough discovery in the genetics of corneal dystrophies

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.

In a landmark paper, published in the international journal American Journal of Human Genetics, they describe alterations in the DNA sequence that affect 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 team used new technological advances in sequencing the human genome to discover the genetic cause. 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. This study is not only important for understanding the cornea in health and disease, but also represents an important major advance in understanding of the ‘non-coding’ regions of the human genome that dictate where, and when, a gene should be switched on or off.

This discovery has paved 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.

The research team was led by Professor Alison Hardcastle and Mr Stephen Tuft at UCL Institute of Ophthalmology and Moorfileds Eye Hospital. Dr Alice Davidson is joint first author of the study and was supported by funding from the Lanvern Foundation, Moorfields Eye Charity and Moorfields Special Trustees. Cerys Evans is joint first author and is a Fight for Sight PhD student working on dominantly inherited corneal dystrophies. 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.