Corneal endothelial dystrophies are a group of inherited eye disorders which affect the endothelium, a thin single layer of specialised cells that line the back of the cornea (front of the eye). The endothelium is vital in maintaining the transparency of the clear surface of the cornea. Corneal endothelial dystrophies can lead to severe sight loss or blindness. For patients who are severely affected, the only treatment currently available is a corneal transplant.
Posterior polymorphous corneal dystrophy (PPCD) is a rare autosomal-dominant form of corneal dystrophy which affects the corneal endothelium. In severe cases, corneal endothelium failure may occur and corneal transplantation is required to restore vision. For many patients with PPCD, the genetic faults are unknown.
The genetic cause of PPCD was discovered by Professor Alison Hardcastle, Dr Alice Davidson and Mr Stephen Tuft at IoO and Moorfields Eye Hospital through the use of a new technological advancement in the sequencing of the human genome. They were supported by Fight for Sight UK and Moorfields Eye Charity.
In a landmark paper published in The American Journal of Human Genetics, the team pinpoints the location of a new PPCD gene and alterations in the DNA sequence that affect a gene called GRHL2. This gene is not expected to be expressed in the corneal endothelium but the team have shown that DNA changes cause the gene to be expressed inappropriately in the corneal endothelial cells. They have discovered that the endothelial cells have an ‘identity crisis’ and transition to a different state leading to dysfunction of the endothelial barrier and resulting in corneal dystrophy.
Professor Hardcastle, a Fight for Sight funded researcher, said: “It was a challenge to identify the DNA alterations causing PPCD because they influence how the GRHL2 gene is regulated. Most other changes in previously identified genes implicated in eye conditions affect the ‘coding’ sequence of the gene. This study is not only important for understanding what is required for a healthy cornea and how it is faulty in disease, but also represents an important advance in human genetics, enhancing our understanding of the ‘non-coding’ regions of the human genome that dictate where, and when, a gene should be switched on or off.”
Neil Meemaduma, Research Manager at Fight for Sight, said: “We are delighted that the results from this study led to the discovery of a new genetic cause of PPCD. This will be the foundation for further studies to understand even more about the biological processes leading to corneal dystrophies and to developing new treatments.”