Dr Allan Richards & Dr Martin Snead
Research description
Rhegmatogenous retinal detachment (RRD; retinal detachment due to holes or tears in the retina) (Fig. 1) is the commonest form of retinal detachment affecting approximately 5,800 new patients per year in the UK in a population drawn principally from the working age group. Even with successful repair, severe residual visual loss, as a result of delayed presentation and poor functional recovery, can remain a significant problem. Consequently retinal detachment contributes to approximately 450 new blind registrations per year for the UK. In contrast to most other blinding retinal disorders, blindness through retinal detachment is potentially avoidable if a rationale for the prediction and prevention of retinal detachment could be developed. This goal has been frustrated by a lack of understanding of the factors influencing retinal detachment even in high-risk groups.
The Stickler syndromes are the commonest inherited cause of retinal detachment and the Vitreoretinal Service at Addenbrooke's Hospital and University of Cambridge provides a regional, national and international tertiary referral service for this disorder. Over 200 families are currently registered as part of this research programme. Affected individuals have a high incidence of RRD, myopia, premature osteoarthritis, deafness and sometimes cleft palate. Most cases of type 1 Stickler syndrome (STL1) have mutations in COL2A1 the gene for type II collagen, a major component of both vitreous and cartilage. These have a characteristic membranous vitreous phenotype.
Many of these mutations result in premature termination of the COL2A1 mRNA and haploinsufficiency, via nonsense mediated decay, an mRNA quality control surveillance system (Fig 2). We were the first group to show that mutations in COL11A1 also result in a form of Stickler syndrome with a beaded vitreous phenotype, known as type 2 Stickler syndrome (STL2). Some families with Stickler syndrome are not linked to either of these genes.
We have recently demonstrated that a family with autosomal dominant RRD also have a defect in the COL2A1 gene. This family lack the systemic features common in Stickler syndrome and have neither the membranous nor beaded vitreous phenotypes, instead exhibiting a disorganised vitreous architecture similar to that seen in sporadic cases of RRD.
- Our research is continuing to explore the genetics of Stickler syndrome including identifying factors that may modify phenotype and linkage studies to discover additional loci.
- Association studies are also being employed to determine the genetic differences that predispose certain individuals to develop RRD in later life.
- Further information including footage of eye surgery can be found at http://www.vitreoretinalservice.org