Professor Graeme Black - research

My major research interest is the investigation of genetic disorders associated with visual disability. The ultimate aims are to improve the diagnosis, management and treatment of such conditions. This work has focused on the characterisation of genes and proteins underlying inherited developmental disorders such as anophthalmia & cataract and retinal degenerative disorders.

Microphthalmia/Anophthalmia spectrum. We have demonstrated that X-linked microphthalmia and Oculo-facial-cardio-dental syndrome are caused by mutation in an X-linked transcriptional regulator, BCOR, which encodes the BCL-6 transcriptional co-repressor. To study BCOR function, we have used morpholino oligonucleotides to knockdown expression of xtBcor in Xenopus tropicalis. This work demonstrated that xtBcor is required for lateral specification and suggests that BCOR is required in normal laterality determination in humans. Work now being undertaken examines how BCOR regulates other genes that are also mutated in human microphthalmia phenotypes.

Corneal dystrophies. We have studied the pathogenetic mechanisms underlying a range of human corneal dystrophies including lattice and granular dystrophies (caused by mutations in the extracellular matrix molecule TGFBI). Here current work is exploreingthe development of novel thereapeutic mechanisms for such conditins. We have also studied the rare blinding disorder Brittle Cornea syndrome.

Best disease and related Retinal Dystrophies Best disease, an autosomal dominant disorder associated with macular visual loss, is caused by mutations in BEST1. The gene product, bestrophin, is a chloride channel located at the basolateral membrane of the RPE. Best disease-causing missense mutations alter chloride ion-related conductance across the RPE cell membrane. By studying genotype:phenotype correlations amongst mutations in BEST1 we have demonstrated that BEST1 mutations also cause autosomal dominant vitreoretinochoroidopathy. Recently we demonstrated that a novel retinal phenotype, autosomal recessive bestrophinopathy, results from biallelic BEST1 mutation. Ongoing studies aim to elucidate the function of the normal protein.

Models of Care for Inherited Eye Diseases The identification of genes causing retinal dystrophies has been highly successful, shedding light on biochemical pathways critical to photoreceptor health. It has expanded the need for genetic testing to support management of affected patients and families. Since 2005 we have provided a national service for genetic testing for inherited retinal dystrophies. Free at the point of contact (funding is provided by Strategic Health Authorities and subject to local priority constraints). Our audit data shows inequality of access to these services. We are currently undertaking research to examine the development of new models of care provision for families with genetic eye diseases. Our current programme aims a) to develop a patient-led, evidenced-based model for providing genetic services to families with inherited retinal dystrophy and b) to evaluate new sequencing technologies for retina dystrophies as current techniques for mutation detection are ineffective for conditions of high heterogeneity such as retinitis pigmentosa.

Outside Manchester

Dr Bart Leroy, Dept of Ophthalmology & Ctr for Medical Genetics, Ghent University Hospital, Ghent, Belgium

Professor AT Moore, Professor SS Bhattacharya, Mr AR Webster Institute of Ophthalmology, UCL, London

Professor Les Biesecker, National Institutes of Health National, Human Genome Research Institute, Human Development Unit, Bethesda, USA

Professor Veronica van Heyningen, Dr David Fitzpatrick MRC Unit of Mammalian Genetics, Crewe Road, Edinburgh.

Within Manchester

Dr Forbes Manson

Professor Dian Donnai, Dr Jill Clayton Smith

Professor Peter Clayton

• RP - Widening Access to Genetic Testing Services.