Directors of Research
MP Snead and Dr A J Richards

Group Members
Annie McNinch and Arabella Poulson.

Postdoctoral Researcher
Dr Laura Towns

Research Registrar
Rebecca Davie
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, delayed presentation and severe residual visual loss, as a result of poor functional recovery, can remain a significant problem and retinal detachment contributes to approximately 450 new blind registrations per year for the UK.
FIG 1 Click to enlarge
In contrast to most other blinding retinal disorders, blindness through retinal detachment is in most cases 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 aim of our research (carried out in the Department of Pathology) is to understand the genetic factors that influence or predispose individuals to develop RRD.

Some inherited disorders have a high incidence of RRD. By identifying the defective genes in these less frequently encountered disorders, we can then examine whether they are also involved in the more common forms of RRD.

The Stickler syndromes are the commonest dominantly 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 180 families are currently registered as part of this research program. The East Anglian medical genetics service will perform fully accredited DNA testing on families characterised as a result of our research.

Affected individuals with Stickler syndrome have a high incidence of RRD, and variable phenotypic features including myopia, premature osteoarthritis hearing loss and cleft palate. 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 mutations resulting in type 1 Stickler syndrome result in premature termination of the COL2A1 mRNA and haploinsufficiency, via the nonsense mediated decay mRNA quality control surveillance system (Fig 2).

FIG 2 Click to enlarge
We were the first group to describe a predominantly ocular form of Stickler syndrome where mutations are sited in exon 2 of COL2A1. This exon is alternatively spliced and not expressed in cartilage. Thus mutations in exon 2 are removed from the mRNA in this tissue, but are retained in mRNA tanscripts expressed in the eye, resulting in the predominantly ocular phenotype.

We were also the first group to show that mutations in COL11A1 also result in a form of Stickler syndrome with a beaded vitreous phenotype, now known as type 2 Stickler syndrome (STL2). (Fig 3)

FIG 3 Click to enlarge
A third, non ocular form, of Stickler syndrome is caused by mutations in COL11A2 which is not expressed in the eye (STL3). Recently, a rare example of recessively inherited Stickler syndrome has been described, with mutations in another collagen gene COL9A1.
These different collagen molecules contribute to the strength of the tissues in which they are expressed, helping to resist tearing forces. They form heterotypic (composite) collagen fibrils which are connected to other components of the extracellular matrix, via type IX collagen which is located on the outside of type II/XI collagen fibrils (Fig 4 collagen fibrils). The collagen fibrils also bind to cells and growth factors such as TGFb1 and BMP-2
FIG 4 Click to enlarge

We have also shown that some families with dominant Stickler syndrome are not linked to any of these genes.

Our current research is progressing in three main areas.

Firstly: We have identified families with Stickler syndrome that are not linked to the known loci for this disorder. We are carrying out linkage analysis using DNA from these family members to identify the gene that is faulty in these families.

Secondly: We are investigating why apparently identical or similar mutations in people with Stickler syndrome can result in a highly variable clinical appearance. Specifically we are testing to see if mutations result in alternative mRNA splicing and so modify the phenotype. We are using minigenes containing either the mutant or normal sequence, expressing these in various cell lines and determining if the mutant produces one or more splice forms. We can then examine whether these differ between the cell lines in which the minigene is expressed. We have used this to demonstrate that the predominantly ocular phenotype can also result from a partial rescue of a mutant donor splice site that can produce some normal mRNA in certain cell lines (Fig5).
FIG 5 Click to enlarge

Thirdly: We are performing genetic association studies. This is comparing natural variation in candidate genes between a population of patients with RRD and a control population. If a particular allele of a gene is a predisposing risk factor it should be more common in the RRD group then controls.

To partake in our research, Patients should obtain a referral to the ophthalmology department Addenbrooke's NHS Trust.

Sponsors of our research have included
  • The Stanley Thomas Research Foundation.
  • The Isaac Newton Trust.
  • The Guide Dogs for the Blind Association.
  • Action Medical Research.
  • The Evelyn Trust.
  • Addenbrooke's NHS Trust.