New form of inherited blindness discovered

Scientists from the University of Leeds, in collaboration with researchers from the Institute of Ophthalmology in London and Ghent University in Belgium, have discovered that mutations in the gene DRAM2 cause a new type of late-onset inherited blindness.

This new insight into the condition was only made possible through collaboration between UK and European institutions. In the UK, the £1.2 million RP Genome Project funded by sight loss charities RP Fighting Blindness and Fight for Sight, brings together leading genetic ophthalmology researcher centres in Leeds, London, Manchester and Oxford.

Results published in the American Journal of Human Genetics describe individuals from five families with a variety of DRAM2 mutations, all of which lead to loss of central vision beginning at age 30-40. Peripheral vision loss is also described in older individuals.

The light-sensing rear surface of the eye (the retina) relays visual information to the brain. It's a complex layered structure, with each layer of cells carrying out clearly defined functions.

DRAM2 has a role in initiating a cell-recycling process called autophagy, in which the damaged components of cells are broken down and renewed.

On discovering a link between DRAM2 mutations and inherited blindness, the authors showed that this protein is found in the retina; in the photoreceptor (light-sensitive) cells, and also at the surface of the retinal pigment epithelium (RPE) layer, where it meets the photoreceptors. RPE cells lie underneath the photoreceptors and take care of these essential cells.

"A high level of autophagy takes place in RPE due to the need for constant renewal of the photoreceptor outer segments following daily light-induced damage" says Dr Manir Ali who led the team making the initial discovery at the University of Leeds. "It is therefore likely that, in the absence of correctly functioning DRAM2, autophagy and photoreceptor renewal is reduced, leading to thinning of the photoreceptor cell layer. Our findings suggest that DRAM2 is essential for photoreceptor survival."

Dr Dolores M Conroy, Director of Research at Fight for Sight, said:

"This is the first paper resulting from our programme to improve patient diagnosis by finding novel disease-causing genes through collaboration between research institutions and in partnership with RP Fighting Blindness. Enabling specific genetic diagnosis is a high priority for research on inherited retinal disease, as identified by the James Lind Alliance Sight Loss and Vision Priority Setting Partnership - a consultation with patients, relatives, carers and eye health professionals."

Sue Drew, Engagement Manager at RP Fighting Blindness, said:

"We welcome this first publication from the RP Genome Project and are delighted real progress is being made. We have been convinced for years that wider research collaboration and partnership working between organisations such as our own and Fight for Sight is the way forward. We are proud to be co-funding the RP Genome Project, which represents a new way of working and progressing IRD research, hopefully paving the way for further collaboration in the sector in the future."

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The research was also supported by grants from the National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology (NIHR Moorfields BRC), the Macular Society UK and the National Eye Research Centre (NERC).

Please cite this article in press as:

El-Asrag et al., Biallelic Mutations in the Autophagy Regulator DRAM2 Cause Retinal Dystrophy with Early Macular Involvement., The American Journal of Human Genetics (2015), http://dx.doi.org/10.1016/j.ajhg.2015.04.006

• Inherited retinal dystrophies (IRD) are an overlapping group of genetically varied conditions resulting from mutations in more than 250 genes.
• IRD affects 1 in every 2000-3000 people.
• IRD can be passed on in a dominant, recessive or X-linked manner.

1. Fight for Sight is the leading UK charity dedicated to funding pioneering research to prevent sight loss and treat eye disease.

2. Fight for Sight is funding research at leading universities and hospitals throughout the UK. Major achievements to date include:

• saving the sight of thousands of premature babies through understanding and controlling levels of oxygen delivery
• restoring sight by establishing the UK Corneal Transplant Service enabling over 52,000 corneal transplants to take place
• providing the funding for the research leading to the world's first clinical trial for choroideremia
• bringing hope to children with inherited eye disease by co-funding the team responsible for the world's first gene therapy clinical trial
• identifying new genes responsible for keratoconus and Nance-Horan syndrome

3. Fight for Sight's current research programme is focusing on preventing and treating age-related macular degeneration, diabetic retinopathy, glaucoma, cataract and corneal disease. We are also funding research into the causes of childhood blindness and a large number of rare eye diseases.

RP Fighting Blindness, registered charity no. 1153851, is an organisation dedicated to finding a cure for retinitis pigmentosa (RP), a hereditary disease of the retina which leads to deterioration of sight and ultimately to blindness. RP affects some 25,000 people in the UK alone. The charity seeks to stimulate and fund cutting-edge medical research and provides information and support services to anyone affected by RP. For further information, please visit http://www.rpfightingblindness.org.uk

The University of Leeds is one of the largest higher education institutions in the UK, with more than 31,000 students from 147 different countries, and a member of the Russell Group research-intensive universities.

We are a top 10 university for research and impact power in the UK, according to the 2014 Research Excellence Framework, and positioned as one of the top 100 best universities in the world in the 2014 QS World University Rankings. http://www.leeds.ac.uk