Fragile X Syndrome
February 28, 2014

Interaction Between RNA And DNA Of Fragile X Gene Causes The Disease

Brett Smith for - Your Universe Online

New research from a team of American researchers has found a genetic mechanism that shuts off the gene associated with fragile X syndrome – which causes developmental disorders such as mental retardation and autism.

According to the team’s report in the journal Science, they were successfully able to a test drug that blocks this blocking mechanism.

While it has been known that the syndrome is driven by the excessive repetition of the certain portion of the genetic code, geneticists haven't known why these repetitions set off the disease.

To reach their findings, the team used donated stem cells from human embryos that tested positive for fragile X syndrome.

"These stem cells were critical to the success of this research, because they alone allowed us to mimic what happens to the fragile X gene during embryonic development," said study author Dilek Colak, a postdoctoral scientist at Cornell University’s Weill Cornell Medical College.

The stem cells were stimulated to become brain cells and at an early point in their development – about 50 days – protein-producing messenger RNA (mRNA) in the cells was seen sticking to the syndrome-causing DNA. This joining made the gene inactive and not able to produce an important protein that facilitates signaling between brain cells.

"Until 11 weeks of gestation, the fragile X syndrome gene is active – it produces its messenger RNA and protein normally. Then, all of a sudden it turns off, and stays off for the rest of the patient's lifetime, causing fragile X syndrome. But scientists have not understood why this gene gets shut off," said study author Samie Jaffrey, a professor of pharmacology at Weill Cornell Medical College. "We discovered that the messenger RNA can jam up one strand of the gene's DNA, shutting down the gene – which was not known before.”

"This is new biology – an interaction between the RNA and the DNA of the fragile X syndrome gene causes disease," he added. "We are coming to understand that RNAs are powerful molecules that can regulate gene expression, but this mechanism is completely novel – and very exciting."

Just before the end of the first pregnancy trimester, messenger RNA manufactured by the disorder gene tends to form an RNA-DNA duplex that produces hundreds of repetitions on a single nucleotide sequence: CGG. This effectively shuts down production of the gene, making it unable to make a protein needed for communication between brain cells.

This gene then remains inactive for life in individuals with fragile X syndrome – which is present in about 1 in 4,000 males and 1 in 8,000 females.

The researchers also developed a drug that binds to CGG in the fragile X gene's RNA before and after the 50-day malfunction. This binding allowed the gene to continue producing its beneficial protein.

"If a pregnant woman is told that her fetus carries the genetic mutation causing fragile X syndrome, we could potentially intervene and give the drug during gestation,” Jaffrey said. “This may delay or prevent the silencing of the fragile X gene, which could potentially significantly improve the outcome of these patients.”

The researchers are now looking for similar RNA-DNA duplexes for other developmental disorders.

"This completely new mechanism by which RNAs can direct gene silencing may be involved in a lot of other diseases," Jaffrey said. "Our hope is that we can find drugs that interfere with this new type of disease process."