Retinal Degeneration and Gene Identification

Our work is divided into two main areas (1) the identification of candidate genes for retinal degeneration and (2) the identification and characterization of non-visual opsins.

Our understanding of inherited retinal dystrophies, a heterogeneous group of disorders, has increased substantially over the last ten years, but many causal genes still remain to be identified. We are using two approaches to identify and characterize novel genes that are involved in photoreceptor function, maintenance and survival which in turn will improve patient screening and help to guide future treatment of these conditions. Firstly using a microarray approach we have established a database of genes that are expressed in rods, cones or both. As well as identifying genes with a known role in the retina we have identified a subset of novel genes with no previously known retinal function. Secondly utilizing the information from large scale sequencing projects in tandem with the well characterised Drosophila phototransduction pathway has enabled us to isolate other genes with unknown function in the mammalian retina. We are characterizing these novel genes and screening patients with retinal degeneration of unknown origin to determine if mutations in these genes give rise to retinal disease.

Ongoing work also includes positional cloning, and the screening of known disease genes, CYP4V2 and IMPG1, in a cohort of patients from Moorfields Eye Hospital and the Western Eye Hospital which will be extended to the Oxford Eye Hospital. A pilot study to examine the genotype/phenotype correlation in patients with diabetic macular oedema has been recently instigated.

Up until a decade ago it was assumed that non-image forming tasks, such as the detection of light for the entrainment of the circadian timing system were performed by rod and cone photoreceptors. The identification of a third type of photosensitive cell in the ganglion cell layer of the retina containing the photopigment, melanopsin (Opn4) has changed the field. Recent work by us has identified two functional isoforms of Opn4 (L and S) in the mouse retina which are expressed in different subsets of retinal ganglion cells (see figure). We are also interested in identifying novel members of the opsin superfamily of G protein coupled receptors such as vertebrate ancient (VA) opsin and Opn3. Recent work has led to the isolation of a VA gene in both the chicken and Xenopus genomes, an unexpected finding as VA was thought to be confined to the agnatha and teleost fish. We demonstrated that in chicken this photopigment is expressed within a population of hypothalamic neurones with extensive projections to the median eminence, the region of the brain containing the deep-brain photoreceptors responsible for daylength detection.

Ongoing work includes the identification of three Opn4 genes in a deep sea fish, Coryphaenoides armatus and a pilot study to determine the role of Opn4 in the sleep-wake dysfunction seen in patients with schizophrenia.