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Upstate researcher makes discovery in the Fragile X syndrome, receives funding to research genomic defects

A new discovery made at Upstate Medical University about the DNA of patients with Fragile X syndrome has been awarded funding from the National Institute of Mental Health (NIMH) for further study.

Researcher Wenyi Feng, PhD, an associate professor of biochemistry and molecular biology, will continue her research on understanding the genome maintenance function of the fragile X protein with a $488,250 grant from the NIMH.

Feng describes her lab’s discovery of a never-reported aspect of the DNA of Fragile X syndrome (FXS) patients as an unexpected result. Her lab is interested in DNA replication, and was working to map the breaks in the DNA of people suffering from FXS. FXS is a genetic disorder that occurs when mutations in the FMR1 gene cause the absence or loss of function of FMRP, a protein needed for brain development.

“It’s important for the human genome because they [DNA] do break, and they’re not at random places,” Feng said. “There are parts of our genome that are more fragile than others, so we want to identify where these non-random places are.”

Feng applied the same stressors to both control DNA and the DNA of a patient with FXS. “It was one of those serendipitous events–we were anticipating that this particular patient and control would share the same kind of breaks elsewhere except for the FMR1 locus on the X chromosome; everywhere else we expected to be equal. We found completely the opposite,” Feng said.

“We had this surprising finding, which suggests that these patients actually have some bigger problems than just that x chromosome site,” she said. “The rest of the genome is also much more fragile than the normal control. So, we decided to try and find out what causes that.”

Feng explains what makes this discovery novel is that they’ve uncovered an additional function of FMRP, besides protein translation. “What we found was that FMRP regulates not only protein translation, but also gene transcription, a step prior to translation—if you compromise transcriptional regulation by FMRP you jeopardize the genome for accumulating abnormal structures called R-loops and causing breaks.”

Feng suggests the reason she and her team were able to uncover this new function. “I think because people weren’t looking for it; they were focusing on the mutation at the FMR1 locus on the X chromosome, which also causes fragility, but only on the X chromosome. The other aspect is that we used a cutting-edge technique to map these breaks, which has a high resolution that the traditional techniques didn’t have.”

These findings were discovered in blood samples; the next step in Feng’s research is to see if there are similar results found in DNA from a patient’s brain.

“Different parts of our body could express different things,” Feng explains. “What you observe in one part of the body may not reflect what is happening in the other.”

They also want to take this finding a step further to try and figure out why these breaks in the DNA appear all over the genome.

“We thought ‘OK, we saw that in patients who have this genome-wide defect; is it because it’s not expressing FMRP? Or is FMRP protecting the genome from genome-wide DNA breakage?’ And so that’s our hypothesis. We think FMRP is a new genome maintenance protein and it prevents excess R-loop formation. We want to figure out how it performs this function.  This new funding will allow researchers to answer that question.

While the discovery has the potential to assist in treatment of FXS in the future—a syndrome that’s hard to treat and has no cure—Feng is taking this research one step at a time.

“I appreciate the complexity of the underlying mutation, which is a repeat expansion in FMR1, that causes FXS, much like the Huntington gene mutation causing Huntington’s Disease—one mutation can cause many defects in other genes,” said Feng. “I think we brought this new aspect (genome protection by FMRP) to the understanding of the Fragile X Syndrome.

“If we are lucky and do find a key target that really can correct a lot of the defects, that would just be icing on the cake.”

Feng is an associate professor of biochemistry and molecular biology at Upstate Medical University. You can read more about the grant here.