UCT Genetic Researchers Do It Yet Again

Human Genetics Researchers within the newly established Institute for Infectious Diseases and Molecular Medicine (IIDMM) at UCT have made a major discovery in the field of genetic blindness. This internationally recognised group, led by Professor Raj Ramesar (Director: MRC Human Genetics Research Unit) and A/Prof Jacquie Greenberg, and which had previously localised two novel genes for retinitis pigmentosa, have identified a specific gene for the locus, known as RP17. The research was conducted in the The genetic defect in South African families was first mapped to the southern tip of chromosome 17 by Soraya Bardien-Kruger to chromosome 17, and formed the basis for her PhD in the Ramesar lab in 1994. The gene hunt, involving five large South African families, led to the unearthing of a gene not previously implicated in human disease, but shown to be expressed in the kidney, lens and choriocapillaris (vascular bed supporting the retina). Dr George Rebello, who co-ordinated the groups findings, and authored the genetics aspect of the manuscript commented that the gene, carbonic anhydrase IV (CA4) is an exciting find because, unlike most other genes found in the retinal degenerative diseases, may be amenable to manipulation, and thus therapy. Claudette Medefindt, National Secretary of Retina South Africa, the lay support group that has funded this research for many years, said that their support of the UCT research group has proven to be immensely positive over the years, and that this finding would spur the research towards therapies in future.

The identification of the gene and genetic defect in the Cape Town laboratory, was complemented by excellent cell biological research in the laboratory of Professor William Sly at the E. A. Doisy Department of Biochemistry, Saint Louis University School of Medicine, University of Missouri in the USA. The latter group, whose work quantified the compromise of CA4 protein function, appear with the UCT group on the latest RP17 publication in the prestigious international journal, Proceedings of the National academy of Sciences (PNAS, USA). Further evidence in support of CA4 as the gene for RP17 comes from its independent identification by Dr Kang Zhang at the University of Utah.

Retinal degenerative disorders are the major cause of inherited forms of blindness. This group of disorders affect individuals at all ages, with macular degeneration being the leading cause of blindness in the ageing population, internationally. Because of the absence of any therapeutics for retinal disorders, new means of addressing potential cures are constantly being sought. Because disorders such as retinitis pigmentosa and macular degeneration are often strongly familial, families have been useful in research aimed at understanding the biology of the disease, postulated as the logical step in trying to find a direct target for therapeutics. Affected individuals from a family will generally share at least that part of their genetic material that carries the gene causing the disease. Geneticists have used this logic to identify a wide range of genes that result in retinal degenerative disorders. To date, approximately 150 genes (out of the total human complement of about 35 000 genes) have been linked to inherited retinal disease. In specific forms of retinal disease, identification of the gene may be the passport to therapeutics. A considerable amount of research is being carried out internationally on different mechanisms of therapeutics including application of specific biological agents to the eye, and gene therapy. Interestingly, even in the same gene, different families will have different mutations. Identification of the defective gene, and the specific mutation in the family will provide the possibility of genetic management, in addition to providing the possibility of aligning those families with the development and trials of potential therapies.

Because of the high level of heterogeneity (i.e. the same disease being caused by any one of several different genes), it has been recognised that a single mode of therapy will not likely be useful for all the RDDs. For this reason, there is pressure to identify the underlying disease genes and genetic defects in as many South African families as possible. Such families, who are ‘genetically characterised’ will be eligible for ‘personalised’ therapies that are being investigated internationally. Already, successful animal clinical trials for a form of childhood retinal disease, Leber’s Congenital Amaurosis (LCA), are to be translated to humans.

A major thrust in the UCT group’s current endeavour is to identify the genetic basis of the most profound forms of inherited retinal diseases usually with the earliest onset (and which are sometimes linked to hearing impairment). It is likely that these forms of disorders will lead to meaningful applications for families in which they occur. In the first instance parents may be offered reproductive choices in the short term, and access to developing therapeutics in the future.

The UCT group has been funded by Retina South Africa, the MRC and THRIP, while Professor Sly’s group has been funded by the NIH.