Overview
The macula is the central part of the light-detecting layer of the eye (the retina). We use it for the detailed straight-ahead vision we need for reading, driving and recognising faces. Although research has discovered lots about what goes wrong in age-related macular degeneration, we don’t yet know much about how the macula develops in humans.
In this project the research team are studying the genetics of three rare inherited eye disorders in which babies are born with damage to the macula. At the moment we don’t know exactly which genes or what types of ‘spelling mistake’ (genetic mutation) are involved. But the team has a large group of patients with these disorders, so the student is pulling together their genetic data and comparing it to data from previous animal work and from stem cells taken from patients.
The aim is to find the genes that cause the disorders. This would mean families could have a specific diagnosis. It will also help us understand more about how future treatments might target the macula.
-
Scientific summary
An investigation of the molecular pathology of developmental macular dystrophies
The project aim is to determine the molecular pathology of a set of three disorders exhibiting a similar congenital ocular phenotype in which the fovea and macular do not develop normally. These include North Carolina Macular Dystrophy, Sorsby Syndrome (in which patients also have a variable degree of hand and foot deformity) and Progressive Bifocal Chorioretinal Atrophy. These disorders link to two chromosomal loci, defined already: MCDR1 on chromosome 6q and MCDR3 on chromosome 5p. The causative genes despite much investigation, remain unknown and so the underlying molecular mechanism may well be unusual.
The team has built up a large resource of patients and families who form the basis of the project. High-density genotype data is available on 120 individuals. Moreover whole genome sequencing data is available for a subset of 25 of these. Analysis of these data is being done to allow the determination of candidate causative DNA variants. Such candidates are then being further analysed using human and macaque retina RNA data, as well as RNA data from iPSC derived patient cells. Depending on the specific variants, the zebrafish model is being investigated for the effect of perturbation of orthologous genes on retinal development.