International consortium, including UCT’s Geneticists identifies novel blindness gene
Researchers from South Africa, Israel, the Netherlands, and the USA report on the identification of a novel gene, IDH3A, which is implicated in an inherited form of blindness, namely retinitis pigmentosa (RP). In the last 25 years, more than 80 genes have been associated with RP and together they explain approximately 70% of all cases. Novel identified genes, such as IDH3A, typically are found in less than 1% of the RP patients. This means that they can only be identified by extensive collaborations between RP researchers worldwide.
In the paper that appeared in Ophthalmology, one family from South Africa, two families from the Netherlands, and one from Israel are reported in which RP patients carry mutations in IDH3A. Together with IDH3B, which was previously associated with recessive RP, and IDH3G, IDH3A forms a protein complex that plays a crucial role in glucose metabolism in mitochondria. Given the fact that IDH3A is important in all human tissues, it is not yet understood why mutations in IDH3A only result in a retinal dystrophy.
A research program investigating inherited retinal disorders (IRD) such as RP in southern Africa was initiated in 1989, in the Division of Human Genetics, University of Cape Town. Working very closely with ophthalmologists around the country and the lay support group, Retina South Africa (who has funded the project since its inception), the Division of Human Genetics has recruited over 3,300 participants from 1500 families. Major milestones of the UCT research group have included the previous identification of two novel RP genes, PRPF8 in 2001 and CA4 in 2004. IDH3A is therefore the third novel gene identified by the UCT team through international collaborations.
There has been a recent emphasis on identifying the genes and mutations causing inherited vision loss in indigenous African families. This was the focus of Lisa Roberts’ PhD project, with the support of the project’s Principal Investigator, and Head of Division of Human Genetics, Prof. Raj Ramesar. Lisa performed whole exome sequencing in the Neurobiology Neurodegeneration & Repair Laboratory (NNRL), at the National Eye Institute in the USA in 2014, under the guidance of her co-supervisor, Dr Anand Swaroop, and his research team. Since Lisa’s work in the USA, the Ramesar Lab in the Institute of Infectious diseases and Molecular Medicine have acquired and fully operationalized a next generation sequencing facility.
Analysing the data generated by this experiment was challenging, particularly as indigenous Africans display vast genetic diversity. Millions of DNA sequence variants were detected, which had to be filtered and evaluated in order to pinpoint the exact mutations causing blindness in the families Lisa was studying. After interrogating all the known IRD genes several of the families remained unresolved. She then examined the genetic sequence data from these unresolved families, looking for variants in a list of candidate genes (including IDH3A), published by the European Retinal Disease Consortium. The identification of multiple families from around the world with mutations in the same gene is strong supporting evidence when trying to link new genes to diseases.
In providing credit to the various roleplayers involved, Prof Ramesar acknowledged the astute role of Dr Gratia Fischer, an ophthalmologist in Johannesburg who provided details of the unusual clinical presentation of the South African individuals with IDH3A mutation All of the research on inherited retinal disorders has the aim of understanding the disease mechanism which leads to visual loss – with the ultimate objective of halting progression of disease, and creating precise molecular interventions.