Since the identification in 1989 of the first gene associated with an inherited retinal disease (IRD) – that gene was RHO, which when mutated, is a frequent cause of retinitis pigmentosa (RP) – genetic researchers, many funded by the Foundation, have identified approximately 270 genes linked to IRDs. In most cases, defects in a single gene can cause a retinal disease and vision loss.
The cumulative breakthroughs in IRD gene discovery over the past three decades are indeed impressive. It means that, today, about 65-70 percent of IRD patients will have their mutated gene identified when getting tested. However, it also means that the gene mutations for about one-third of patients are still not identified.
To address the gap in genetically diagnosing patients, the Foundation is funding a 5-year, $2.5 million project to find elusive IRD genes and mutations.
“Patients benefit greatly from the identification of their disease-causing gene mutations. It confirms their diagnosis, identifies risk for other family members, and is often helpful for qualifying for clinical trials,” says Stephen Rose, PhD, chief scientific officer, Foundation Fighting Blindness. “The results from the elusive genes project will ultimately help us get more people diagnosed and on a better path for managing their condition. It will also help researchers develop treatments that can help more people.”
“A strategic goal of the Foundation has been to find the underlying cause of disease in at least 95 percent of patients with inherited retinal diseases,” says Stephen Daiger, PhD, a genetic researcher at the University of Texas in Houston, working on the elusive genes project. “We’re almost there. We’re finally in the end stage of understanding the causes of inherited retinal diseases, in my opinion.”
The elusive genes research effort will also include Radha Ayyagari, PhD, the project lead at the University of California, San Diego, and Kinga Bujakowska, PhD, a retinal geneticist working with Eric Pierce, MD, PhD, at Massachusetts Eye and Ear.
In addition, David Gamm, MD, PhD, at the University of Wisconsin-Madison, will use induced pluripotent stem cells (stem cells derived from patients’ skin or blood) to create IRD models for studying expression in newly identified genes to determine if a defect is actually causing the disease.
The study will include more than 140 families and an additional 400 individuals.
Investigators will be looking for ultra-rare IRD genes yet to be discovered, as well as hard-to-find defects in known genes.
“To find the very rare genes, we need to conduct studies in large numbers of patients,” says Dr. Ayyagari. “Once we find a possible IRD gene, we need to study it in a cell or animal model to determine if it is truly critical to retinal health and function.”
A deep dive into elusive gene mutations
Genes (DNA) are like recipes that cells use to make proteins. Proteins are essential to the health, survival, and function of our cells. The recipes are delivered to protein-making machinery in the cell through messages (RNA). If there is a mistake in the DNA or the RNA, then the cell will make the wrong or too little protein, and bad things happen to the cell.
Most disease-causing mutations occur in regions known as exons. Exons are like instructions in a recipe: “Add 1 tablespoon of yeast.” In simple terms a mutation in an exon might be a misspelling like: “Add 1 tablespoon of xeast.” While no mutation is easy to locate, simple misspellings in exons are the most obvious place to find them – that’s where researchers look first.
However, sometimes entire instructions in DNA are either missing or duplicated. These mistakes are difficult to identify.
Difficult-to-find mutations can also occur in introns, which are regions between the instructions (i.e., between the exons). On some occasions, there is too much space, or not enough, between the instructions. These intronic mutations can lead to mistakes in creation of the messages (RNA).
Think of it as if the assistant in a bakery copied down the recipe incorrectly from a book, because there were two instructions on the same line. The master baker, in receiving the incorrect message from the assistant, makes a bread that doesn’t rise.
A final thought
Keep in mind that a person’s entire collection of DNA, their genome, is comprised of about 6 billion letters. That alone often makes finding new disease-causing mutations a very challenging endeavor.