Press Release: International consortium, including UCT’s Geneticists, identifies novel blindness gene

Researchers from South Africa, Israel, the Netherlands, and the USA have identified a novel gene which is implicated in an inherited form of blindness, namely retinitis pigmentosa (RP). The gene, called IDH3A, is the third novel gene identified by the Division of Human Genetics, University of Cape Town, in collaboration with international partners. IDH3A is important in all human tissues, but it’s mutations only result in degenerative retinal disease (dystrophy), the cause of which is not yet understood.

The findings, published in Ophthalmology, report one family from South Africa, two families from the Netherlands, and one from Israel in which RP patients carry mutations in IDH3A.

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.

The Division of Human Genetics has been researching inherited retinal disorders (IRD) such as RP in southern Africa since 1989. 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 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.

“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,” says Head of Division of Human Genetics, Prof. Raj Ramesar.    

One of the co-authors of the Ophthalmology paper, PhD student Lisa Roberts, focused on identifying the genes and mutations causing inherited vision loss in indigenous African families. 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. Whole exome sequencing is a next-generation sequencing technique which allows the simultaneous sequencing of all the exons (i.e. the coding portions of genes) in the genome.

“Analysing the data generated by this experiment was challenging, particularly as indigenous Africans display vast genetic diversity,” says Lisa. “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 I was studying.”

After interrogating all the known IRD genes, several of the families remained unresolved. Lisa 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.

“Although there were various roleplayers involved,” says Prof Ramesar, “ I want to acknowledge 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.”

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. This allows high-throughput sequencing like the Whole Exome Sequencing.