New genetic clues found in fragile X syndrome

Scientists have gained new insight into fragile X syndrome -- the most common cause of inherited intellectual disability -- by studying the case of a person without the disorder, but with two of its classic symptoms.

In patients with fragile X, a key gene is completely disabled, eliminating a protein that regulates electrical signals in the brain and causing a host of behavioral, neurological and physical symptoms. This patient, in contrast, had only a single error in this gene and exhibited only two classic traits of fragile X -- intellectual disability and seizures -- allowing the researchers to parse out a previously unknown role for the gene.

"This individual case has allowed us to separate two independent functions of the fragile X protein in the brain," said co-senior author Vitaly A. Klyachko, PhD, 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."

The research, appearing in the Proceedings of the National Academy of Sciences (PNAS) Online Early Edition in December and in the print issue Jan. 5, is by investigators at Washington University and Emory University School of Medicine in Atlanta.

In studying fragile X, researchers' focus long has been on the problems that occur when brain cells receive signals. Like radio transmitters and receivers, brain cells send and receive transmissions in fine tuned ways that separate the signals from the noise. Until recently, most fragile X research has focused on problems with overly sensitive receivers, those that allow in too much information. The new study suggests that fragile X likely also causes overactive transmitters that send out too much information.

"The mechanisms that researchers have long thought were the entirety of the problem with fragile X are obviously still very much in play," Klyachko said. "But this unique case has allowed us to see that something else is going on."

The finding also raises the possibility that drugs recently tested as treatments for fragile X may be ineffective, at least in part, because they only dialed down the brain's receivers, presumably leaving transmitters on overdrive.

Fragile X syndrome results from an inherited genetic error in a gene called FMR1. The error prevents the manufacture of a protein called FMRP. Loss of FMRP is known to affect how cells in the brain receive signals, dialing up the amount of information allowed in. The gene is on the X chromosome, so the syndrome affects males more often and more severely than females, who may be able to compensate for the genetic error if their second copy of FMR1 is normal.

Patients with fragile X have a range of symptoms. One of the mysteries of the syndrome is how loss of a single gene can lead to such a variety of effects in different patients. Some patients are profoundly intellectually disabled, unable to talk or communicate. Others are only mildly affected. Patients often experience seizures, anxiety and impulsive behavior. Typical physical symptoms include enlarged heads, flat feet and distinctive facial features. Almost one-third of patients with fragile X also show symptoms of autism spectrum disorders.

To gain insight into what else FMRP might do, the researchers plumbed genetic sequencing data from more than 900 males with intellectual disabilities but without classic fragile X syndrome. They looked for mutations in the FMR1 gene that might impair the protein but not eliminate it entirely. Even in this relatively large sample size, they only found one patient with abnormal FMRP, resulting from a change in a single letter of the gene's DNA code.

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New genetic clues found in fragile X syndrome