UI Research Team Finds New Genetic Cause of Blinding Eye Disease

Tuesday, August 9, 2011

Combining the expertise of several different labs, University of Iowa researchers have found a new genetic cause of the blinding eye disease retinitis pigmentosa (RP) and, in the process, discovered an entirely new version of the message that codes for the affected protein.

Included in the research team are Todd Scheetz, associate professor of biomedical engineering and researcher at the Center for Bioinformatics and Computational Biology.

The study, which was published online Aug. 8 in the Proceedings of the National Academy of Sciences (PNAS) Early Edition, 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 replacement approaches.

Using 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). This 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 stem 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.

RP is an uncommon, inherited blinding eye disease that affects about 1 in 4,000 people in the United States. It 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 Edwin Stone, M.D., Ph.D., 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. This 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.

Based on the new work, the UI team hopes to explore gene therapy and cell replacement strategies as potential therapies for this form of RP.

The study was funded in part by grants from the National Eye Institute, National Institutes of Health New Innovator Award program and the Foundation Fighting Blindness.