NEK2 Identified as New Retinitis Pigmentosa Gene

September 25, 2013

An international research team funded by the Foundation used a cutting-edge technique called whole genome sequencing (WGS) to identify defects in the gene NEK2 as a cause of autosomal recessive retinitis pigmentosa (arRP). The investigators conducted follow-up studies of NEK2 in zebrafish to better understand how mutations in the gene lead to vision loss. Ultimately, discovery of the gene’s link to arRP enables researchers to genetically diagnosis more patients than before. It also provides potential targets for the development of vision-saving therapies for those affected by NEK2 mutations. Results of the study were published in the journal Proceedings of the National Academy of Sciences (PNAS).

WGS is a powerful technique for finding disease-causing genes. Carlo Rivolta, Ph.D., the study’s lead scientist, of the University of Lausanne in Switzerland, says that WGS can identify more mutations than whole exome sequencing (WES). The latter targets only the genetic regions where harmful mutations are thought to frequently occur, those that code for proteins which are critical to the health and function of all cells in the body. However, WGS is more costly and complex than WES.

“Whole-exome sequencing covers about 1.5 percent of the genome, specifically all coding regions, whereas whole-genome sequencing covers 98 percent, including the coding regions,” says Stephen Daiger, Ph.D., a retinal-disease geneticist at the University of Texas Health Science Center. “The cost of WGS is coming down, and the research emphasis is on improved technology, using a variety of platforms. Since WGS is the wave of the future, it’s probably smart to the ride the wave. With that said, WES is by no means out of date. It remains a powerful and efficient tool for gene and mutation discovery.”

In addition to linking NEK2 to arRP, the study’s investigators found new mutations in seven other genes that had been previously linked to arRP, including: USH2A, RDH12, CNGB1, EYS, PDE6B, DFNB31 and CERKL. Knowledge of these new mutations will also help genetic laboratories diagnose more patients with arRP.

The study investigators performed WGS on 16 patients — eight Americans and eight of Japanese ancestry. Dr. Rivolta says that it was important for his team to include patients from both Western and Eastern populations, because they are often affected by different mutations.

“Most of what we previously discovered about the molecular genetics of RP is based on findings from patients of European ancestry,” says Dr. Rivolta. “Analyzing patients from different parts of the world gives us new insights into the geographical dimension of RP genetics.”

While more than 50 genes have been linked to arRP and related recessive conditions, such as Usher syndrome, genetic labs and researchers can find the disease-causing genetic mutation in only about 40 percent of those affected by arRP.

“Finding new disease-causing genes and mutations is critical to diagnosing patients with retinal diseases and developing the best therapies for them,” says Dr. Rivolta. “We need to continue to be creative and inclusive in the search for new mutations and use the most powerful technologies available.”