The genetics of conditions that affect the cornea’s inner lining

Research details

  • Type of funding: Early Career Investigator Award
  • Grant Holder: Dr Alice Davidson
  • Institute: UCL Institute of Ophthalmology
  • Region: London
  • Start date: October 2015
  • End Date: March 2019
  • Priority: Causes
  • Eye Category: Corneal & external

Overview

The corneal endothelial dystrophies (CED) are conditions with various symptoms and different genetic causes. They all affect a thin layer of specialised cells (known as the endothelium) that line the back of the clear front surface of the eye (the cornea). They can all lead to serious sight loss.

Fuchs endothelial corneal dystrophy is the most common CED. It affects around 4 in 100 over-40s. Others are very rare. Some of the genes linked to CED have been discovered, but we don’t necessarily know their role in healthy or unhealthy eyes. Some genes haven’t been found yet.

In this project, the researcher is analysing DNA samples from a large group of CED patients at Moorfields. The aims are to identify known and new genetic causes of CED and to find out whether there's an overlap of relevant genes between common and rare types of CED. Finally, the researcher will try to find out exactly how particular genetic faults cause corneal endothelial cells to fail, using cells from patients.

Results from the project will mean that more people can be given a precise genetic diagnosis. This will mean they can have better genetic counselling about how their condition might affect themselves and their family and perhaps help them spot symptoms earlier. The results could also provide a ‘biomarker’ test that could identify people at risk from CED, as well as providing future targets for treatment.

  • Scientific summary

    Genetic and molecular dissection of corneal endothelial dystrophies

    Corneal endothelial dystrophies (CEDs) are a group of clinically and genetically heterogeneous disorders that can lead to bilateral severely impaired vision or blindness. CEDs include the complex genetic disorder Fuchs’ endothelial corneal dystrophy (FECD) and the monogenic diseases, congenital hereditary corneal dystrophy (CHED) and posterior polymorphous corneal dystrophy (PPCD). FECD alone is estimated to affect more than 4% of people over 40 years of age and accounts for over 1,000 corneal transplantation procedures per year in the UK.

    Corneal transplantations are currently the only treatment option available for CED patients with advanced disease and alternative treatment strategies and/or therapies are urgently required. Dr Davidson's research aims to identify currently unsolved genetic mechanisms and genes associated with CEDs, in addition to determining underlying pathological mechanisms so that this knowledge, in the longer-term, can be harnessed to develop alternative treatment strategies.

    An extensive cohort of CED patient DNA samples has already been recruited to the study, and using a variety of next generation sequencing technologies in combination with classical molecular biology techniques, Dr Davidson is aiming to identify novel genetic causes of disease, providing patients with accurate molecular diagnoses and revealing novel and potentially unifying insights into disease mechanism. CED-associated mutations are being studied in cellular and genomic context using cultured patient-derived corneal endothelial cells and histological specimens, in order to enhance understanding of the potential functional interplay between the genes implicated with CEDs and how, when perturbed, they lead to endothelial cell dysfunction