Researches find new genetic cause of RP

The study, which was published in the Proceedings of the National Acady of Sciences, suggests that the mutation may be a significant cause of RP in people of Jewish descent.
The findings also lay the groundwork for developing prevention and treatment for this form of RP using a combination of genetic testing, gene therapy and cell replacent approaches.
Researchers find new genetic cause of RPUsing the latest DNA sequencing techniques to analyze the protein-coding regions of a single RP patient’s genome, the researchers found a mutation in a gene called MAK (male germ cell associated kinase). That gene had not previously been associated with eye disease in humans.
However, examining tissue from donated eyes showed that MAK protein was located in the parts of the retina that are affected by the disease.
The researchers then generated induced pluripotent st cells (iPSCs) from the patient’s own skin cells and coaxed these immature cells to develop into retinal tissue. Analyzing this tissue showed that the gene mutation caused the loss of the MAK protein in the retina.
“These new technologies have greatly enhanced our ability to find and validate disease-causing mutations, which is critical to our ability to progress to the next step of actually treating diseases like RP,” Dr Budd Tucker, PhD, UI assistant professor of ophthalmology and visual science, and lead study author, said.
RP is thought to be caused by mutations in more than 100 different genes, only half of which have been identified.
Having found the MAK mutation in one patient, UI researchers led by Dr Edwin Stone, MD, PhD, a Howard Hughes Medical Institute investigator and director of the UI Institute for Vision Research, screened the DNA of 1,798 patients with RP and identified 20 additional individuals with the same MAK mutation.
That result suggests that the new MAK mutation accounts for about 1.2 percent of RP cases in the general population. Interestingly, all 21 of the RP patients with the MAK mutation were of Jewish descent, suggesting that the mutation may be a significant cause of RP in this population.
Work in the laboratory of Dr Robert Mullins, PhD, UI associate professor of ophthalmology and visual sciences, showed that MAK protein was produced in the cells most affected by RP. These findings prompted Dr Tucker and colleagues to make iPSCs from the original patient.
“Induced pluripotent st cells allow us to generate affected tissue from patients with genetic disorders and analyze how specific genetic mutations cause disease,” Dr Tucker said.
“It’s particularly powerful when we are looking at inaccessible tissues such as the retina and brain which are not usually biopsied in living individuals.”
Although the MAK gene was previously thought to have 13 protein-coding segments known as exons, when the UI team cloned and sequenced the MAK gene, they discovered a new version of the gene found only in the retina, which has an extra protein-coding exon.
The team also found that the MAK mutation, which involves an insertion of a large piece of DNA into the MAK gene, disrupts the gene in such a way that retinal cells lose the ability to make the longer version of MAK protein.
“What we found was a new retina-specific exon; no other tissue that we tested had this version of the protein-coding transcript,” Dr Tucker said.
“That is important because the gene mutation identified prevents the production of the retina-specific MAK protein.
“Evidence from the iPSC work validated the role of this genetic mutation in retinal disease. Showing that retinal cells generated from the affected patient could not make the mature retinal MAK protein provided strong evidence of the pathophysiologic mechanism of this mutation in RP,” Dr Tucker explained.
Based on the new work, the UI team hopes to explore gene therapy and cell replacent strategies as potential therapies for this form of RP.