Genetic error highlights a new approach to Fragile X syndrome

Fragile X has loomed large as a frustrating target in drug discovery. Experimental therapies that appeared promising early on have failed in the clinic, spurring investigators to dig deeper into the triggers for this inherited intellectual disease. And now a team of investigators say that a single mutation in the gene linked to Fragile X--which is the largest single-gene cause of autism--can be tied to specific symptoms of the disease, suggesting that a new approach to treating the disease could work where others have failed.

The insight came after a group at Washington University and Emory University School of Medicine in Atlanta drilled down into sequencing data from 900 patients with some common intellectual disabilities but without the full set of classic symptoms used to diagnose Fragile X. They found one patient with a single error in the FMR1 gene. The disabled FMR1 gene disrupts the production of the FMRP protein, which regulates cell signaling in the brain. Once it's lost then signaling receivers in the brain take in too much information, scrambling the signals.

But the investigators wanted to find out what happens when you impair the protein, rather than eliminate it. After tracking down the rare mutation in a single patient with two intellectual disabilities but none of the classic symptoms associated with autism, they created animal models that allowed them to further probe its effect. And they concluded that even with the mutation the cell receivers were operating normally.

What the mutation did do, say these researchers, is to increase the number of cell transmitters, the signal broadcasts that are needed to keep the brain functioning normally. And that raises the distinct possibility that earlier research centered on the receivers may have failed to account for a key disruption--with an excess amount of signals being sent--that should be addressed by a new therapeutic research.

Vitaly Klyachko

"This individual case has allowed us to separate two independent functions of the Fragile X protein in the brain," said co-senior author Vitaly Klyachko, associate professor of cell biology and physiology at Washington University School of Medicine in St. Louis. "By finding the mutation, even in just one patient, and linking it to a partial set of traits, we have identified a distinct function that this gene is responsible for and that is likely impaired in all people with Fragile X."

- here's the release

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