Newly Found Gene is Common Cause of RP in People of Jewish Descent

August 11, 2011

A Foundation-funded research team, led by the University of Iowa, has identified a defect in the gene MAK as a prevalent cause of autosomal recessive retinitis pigmentosa (arRP) in people of Ashkenazi (Eastern European) Jewish descent.

Researchers at the University of Iowa’s Carver Lab used whole-exome sequencing — a screening approach that targets the genetic regions where disease-causing defects are most likely to occur — to identify a MAK defect as the cause of arRP in an individual with Ashkenazi descent. After subsequently screening the DNA of 1,798 people with arRP, they found that the MAK defect was the cause of disease in 20 additional people, all of whom have Ashkenazi heritage.

A Foundation-funded research team headed up by the Radboud University Nijmegen Medical Centre in The Netherlands also used whole-exome sequencing to identify a MAK variation as the cause of arRP in one Turkish individual. They subsequently found MAK defects as the cause of arRP in two Dutch and three Israeli individuals. The three Israeli subjects have Jewish ancestry.

As a result of the finding, the Iowa investigators are now working toward treatment options for this form of RP including gene therapy, cell-replacement therapy and potentially a combination of the two.

The Carver Lab is also offering a genetic test for the MAK gene as part of their arRP genetic screening portfolio.

“Thanks to this effort, we now know that MAK defects are clearly a frequent cause of RP in people of Ashkenazi descent,” says Stephen Rose, Ph.D., chief research officer, Foundation Fighting Blindness. “This information will help us better diagnose more people in this ethnic group, and most importantly, identify treatment targets for them.”

As part of their research into the MAK gene, the Iowa researchers are using induced pluripotent stem cells — stem cells derived from the skin of an affected person — to replicate the disease in a dish and confirm that MAK defects are in fact causing RP. In a two-step process, the skin cells were reverted back to a stem cell fate and then coaxed forward to become retinal cells. The investigators are now evaluating the genetic and functional activity of the newly derived retinal cells to better understand MAK’s role in the disease process.

MAK appears to affect the development and function of cilia, hair-like structures within photoreceptors that serve as a transport system for critical proteins and biochemicals. Ciliary defects cause a number of retinal degenerative conditions including Usher syndrome and various forms of RP and Leber congenital amaurosis.

“The MAK project illustrates how different areas of research often work together toward the development of a treatment. Advances in genetic discovery and stem cell technologies along with a better understanding of retinal biology have all played a role in this effort,” says Dr. Rose. “What’s most impressive is how quickly we applied this knowledge. In a matter of months we moved from genetic screening to investigating therapeutic options. Retinal research is accelerating at a remarkable pace.”

Results of the University of Iowa’s MAK-related screening and research were published on August 8, 2011 in the online edition of the Proceedings of the National Academy of Sciences.

Results of the Nijmegen Medical Centre’s research were published on August 12, 2011 in The American Journal of Human Genetics.