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Scientists Discover Genetic Cause of Autosomal-Dominant Corneal Dystrophy

Posterior polymorphous corneal dystrophy (PPCD) is a rare autosomal-dominant disorder, primarily affecting the corneal endothelium and Descemet membrane. Whereas mild manifestations of the disease include asymptomatic corneal endothelial changes such as vesicular, band-like, and geographic lesions, severe cases involve corneal endothelial failure which necessitates transplantation to restore vision.

PPCD is a genetically heterogeneous condition, with approximately a third of cases attributed to heterozygous mutations in the transcription factor encoding gene ZEB1. Now, researchers at the at the University College London have pinpointed the location of a new PPCD gene and alterations in the DNA sequence that affect a gene called GRHL2.

The gene is not normally expressed in the corneal endothelium, but the researchers found that DNA changes cause the gene to be expressed inappropriately in the corneal endothelial cells. The team 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.

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