Investigation and treatment of intronic ABCA4 mutations in patients with inherited retinal dystrophy

Overview

Inherited retinal disease is now the most common cause of blind registration in working-age people in the UK (Liew et al). These disorders are due to changes in the DNA code (mutations) of many different genes in affected persons. The most common such gene, which accounts for approximately one third of clinic visits to specialist inherited retinal clinics is ABCA4. This causes a spectrum of retinal disorders including Stargardt disease, macular dystrophy and cone-rod dystrophy.

A proportion of the causative mutations include those that occur within introns of the gene, the segment of a DNA or RNA molecule which does not code for proteins and interrupts the sequence of genes. These are parts of the gene that are removed as the gene is expressed in the specific cell, before the protein is made.

Most mutations occur in exons and subtly change the encoded protein. However, a significant number occur in introns and can cause the creation and inclusion of an abnormal pseudo-exon, which rejects normal gene expression.

This proposal builds on a large cohort of patients presenting to Moorfields eye hospital of which a significant number have intronic mutations. The aim is to identify new intronic mutations and determine a strategy to follow these new variants and their ability to cause disease. This research has the potential to increase the ability of clinicians to diagnose or confirm the clinical suspicion of diseases of the retina due to ABCA4 mutations.