Scientists discover Kabuki syndrome treatment

Kabuki syndrome, a newly-discovered genetic disease, has been the subject of several studies aimed at determining its causes and finding potential medications for treating the disease. Recently, a team at the School of Medicine has discovered a potential route for developing drugs that can treat the disease.

Genetic disorders arise from mutations in genes. These mutations are either inherited or occur after fertilization of the egg by sperm. While genetic disorders such as Down syndrome are more well-known, other genetic diseases — though debilitating — are less well-known because of their rarity. Kabuki syndrome is one of these more obscure diseases and only appears in one out of every 32,000 births.

The disease was first identified by Japanese scientists in the beginning of the 1980s. The scientists, Norior Niikawa and Yoshikazu Kuroki, named the disease Kabuki syndrome because those affected by the disease have faces that resemble performers with Kabuki makeup. The afflicted children often have hearing loss, growth deficiency and heart defects. In addition, 92 percent of Kabuki patients suffer from intellectual disability.

Scientists determined that the cause of Kabuki syndrome resides in a mutation in the gene MLL2. The mutation causes MLL2 to lose its regular function.

MLL2 is a gene that controls the way DNA wraps around histones, forming structures called chromatins. The densely compacted DNA allows the cell to store a lot of genetic information within its nucleus. However, when DNA is compacted so densely, the cell needs special enzymes to unzip the wrapped DNA to perform regular cellular functions such as synthesizing proteins. These enzymes enable the cell to both unwrap the DNA for copying and rewrap it afterwards. Due to the MLL2 mutation, these enzymes cannot do their job properly.

The MLL2 mutations disable the cell’s ability to access DNA. Therefore, the researchers, led by Hans Bjornsson, an assistant professor of pediatrics and genetics at the School of Medicine’s McKusick-Nathans Institute of Genetic Medicine, sought to alleviate the effects of Kabuki syndrome by altering the accessibility of DNA to the cell.

In one experiment, mice affected with a disease similar to Kabuki syndrome were treated with an anticancer drug called AR-42. Originally, AR-42 was developed for blood cancer, but it is also known for providing access to compacted DNA. The mice underwent a two-week regimen and then were evaluated using a Morris water maze. The maze consists of a large pool of water and a platform that is submerged. To escape the maze, the mice need to find the platform through memorization of some or all of the following: actions needed to reach the platform, visual hints or correct spatial orientation. Because of the importance of memory in the navigation of the maze, researchers often use the Morris water maze as an assessment of memory.

In the comparison between mice treated with AR-42 and the untreated Kabuki syndrome-like mice, scientists discovered that AR-42 improved the development of neurons in the hippocampus. Mice treated with the anticancer drug were more developed in the dentate gyrus, a region responsible for the formation of memories. As a result, mice that were treated with AR-42 are better equipped to memorize the necessary actions and cues for the completion of the Morris maze.

Although the results of the studies suggest a possible drug for the treatment of Kabuki syndrome, the drug may take years to develop. However, this study and many others challenge the perception that the symptoms of genetic disorders have to be permanent.