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How does molecular/genetic ophthalmic research benefit the clinician? If this question had been asked 10 years ago the answer would have been quite different from that of today. At that time very few ocular genes were known. The main aim of laboratory research was to establish linkage for an inherited disorder to a specific chromosomal region for a family. This allowed the early identification of members of a family who were at risk of being affected. Even this type of work was limited to conditions such as gyrate atrophy, cataracts, and retinitis pigmentosa, because linkage work was still very much in its infancy.
In 1999 there are over 60 ocular genes identified.1A clinician can request not just linkage information but specific mutation screening for many inherited ocular diseases, ranging from corneal dystrophies to Norrie’s disease. Because of limited funding, much of this work is performed at the research level only and not widely available as a laboratory service. The clinician can, however, use these data to counsel patients far more accurately and request prenatal testing.
Over the next 10 years it would be reasonable to anticipate the completion of the human genome mapping project and the identification of many more genes responsible for ocular disease. At this time the clinician might reasonably ask not only for specific mutation information but also to be advised on new therapies that might be available. In some cases this may involve gene therapy, in others it might be replacement of a protein deficient in individuals deemed to be at risk of developing the disease. Alternatively, it may be that for diverse diseases such as glaucoma, one particular subgroup—for example, GLC1A, may be shown to respond better to medical treatments than surgical. With this knowledge the clinician can instigate the best and most appropriate therapy.
Having established that a rudimentary knowledge of molecular and genetic ophthalmology is important to the clinician, it is refreshing to see research, that a couple of years ago would have been published only in the scientific journals, now appearing in the ophthalmic literature. In this issue of the BJO,Nishina and colleagues (p 723) discuss the pattern of expression of a gene central to the development of the eye. This work is important because it is the first time that human embryos have been studied as late as 22 weeks’ gestation. Previous work has focused mainly on animal or very early human embryos.2 The gene under study in this paper (PAX6) is fascinating because it has changed very little throughout evolution. In fact, the mouse and human gene products differ by only one amino acid.3 PAX6 is not only expressed in the eye but also in the developing pancreas and CNS.4 The regulation of PAX6 expression is largely unknown but recent studies in mice have shown that the gene contains two distinct promoters, P0 and P1, that control the level ofPAX6 in specific tissues. For example, P0 activation produces transcripts predominately in the lens, cornea, and conjunctival epithelium, whereas P1 initiated transcripts are expressed in lens, optic vesicle, and CNS. Other regulatory elements exist within the PAX6 gene that require stimulation for expression to occur in the pancreas or in particular subsets of retinal cells.5
The PAX6 gene is thought to be at the top in the hierarchy of genes that determine when and how different parts of the eye differentiate. The exact pathways have yet to be elucidated but Nishina et al suggest some of the genes that are likely to be involved in this cascade. It is interesting that the PAX6 gene is widely expressed in ectodermal but not mesenchymal structures because mutations in PAX6 give rise to abnormalities in tissues derived from mesenchyme—for example, aniridia and Peters’ anomaly. Nishina and colleagues propose explanations for these and other PAX6 disorders, suggesting that the PAX6 protein targets other genes that may be expressed in, or control the differentiation of, these tissues, such as neural cell adhesion molecule (N-CAM), crystallins, and other retinal homeobox genes. IfPAX6 is at the top of the pyramid one might expect that gene mutations could affect virtually any part of the eye via its interactions. Several PAX6 screening studies are under way to identify mutations in a variety of different developmental conditions (GC Black, St Mary’s Hospital, Manchester; IM Hanson, MRC Human Genetics Unit, Edinburgh; AJ Churchill, St James’s Hospital, Leeds, unpublished data). To date,PAX6 mutations have been found to cause aniridia, dominant keratitis, Peters’ anomaly, foveal hypoplasia, and congenital cataracts.6 Only a minority of cases of Peters’ anomaly are, however, due to PAX6mutations and it will be interesting to see if screening some of the proposed target genes reveals new mutations in this and other congenital disorders.7
If PAX6 controls and orchestrates ocular development why does expression continue in the adult corneal and conjunctival epithelium? Nishina et alsuggest that normal PAX6 protein may be necessary for the maintenance of a healthy cornea in that haploinsufficiency can result in keratitis. A similar picture is not infrequently seen in aniridics where minor epithelial trauma may be followed by a poor healing response with apparent stem cell failure. If a critical concentration of PAX6 protein is required for corneal health then it may not be beyond the realms of possibility to synthesise the protein and administer it in topical form to those patients with apparent stem cell failure.
There is a fundamental need for close collaboration between clinicians and scientists to maximise research potential. The paper by Nishinaet al is an example of a successful multidisciplinary team effort. Clinicians must stay abreast of scientific advances to improve such links with laboratory based colleagues and thereby fully appreciate what molecular/genetic research has to offer.