A new genetic cause of an autosomal-dominant corneal endothelial dystrophy has been discovered in a study led by University College London scientists.
Posterior polymorphous corneal dystrophy is a rare autosomal-dominant disorder, primarily affecting the corneal endothelium and Descemet membrane. Image credit: Pexels.
Corneal endothelial dystrophies are a group of inherited eye disorders which affect the endothelium, a thin single layer of specialized cells that line the back of the cornea, 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.
In a paper published in the American Journal of Human Genetics, University College London’s Professor Alison Hardcastle and colleagues pinpoint 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 researchers found that DNA changes cause the gene to be expressed inappropriately in the corneal endothelial cells.
They 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.
“It was a challenge to identify the DNA alterations causing PPCD because they influence how the GRHL2 gene is regulated,” said Professor Hardcastle, a Fight for Sight funded researcher.
“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.”
“We are delighted that the results from this study led to the discovery of a new genetic cause of PPCD,” said Dr. Neil Meemaduma, research manager at Fight for Sight who was not involved in the study.
“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.”
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P. Liskova et al. 2018. Ectopic expression of GRHL2 due to non-coding mutations promotes cell state transition and causes Posterior Polymorphous Corneal Dystrophy 4. Am J. Hum Genet 102 (3): 447-459; doi: 10.1016/j.ajhg.2018.02.002
