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fragile X syndrome

Fragile X discovery may clarify root cause of symptoms

Discovery of a previously undetected link between the gene that causes fragile X syndrome and uncontrolled tissue growth could shed light on what’s behind the physical and mental impairments the disorder causes, researchers report.

An inheritable genetic condition, fragile X syndrome is estimated to cause mild to moderate intellectual disabilities in 1 in 4,000 to 5,000 males and 1 in 6,000 to 8,000 females. It also causes physical abnormalities such as large brain size and weight at birth, unusually fast growth in height, gastrointestinal issues, and a high risk of obesity.

For the study, scientists removed the same protein that’s missing in people with fragile X syndrome from the intestines of fruit flies to model the disease.

intestinal samples from fruit flies
This image shows four intestinal samples from fruit flies. The normal-sized intestine appears in white. A larger-than-average intestine with a mutated FMR1 gene appears in red. A smaller-than-average intestine with a mutated LIN-28 gene appears in green. A sample from a fly with both mutations appears in yellow. (Credit: Arthur Luhur/Indiana U.)

“To our knowledge, this is the first study to find a stem-cell-based mechanism by which a protein that is absent in people with fragile X syndrome limits excessive organ growth,” says lead author Arthur Luhur, a research associate in the biology department at Indiana University. “This could represent a root cause for the gastrointestinal problems seen in people with the condition.”

Similarly, Luhur says the stem-cell-based mechanism could cause symptoms seen in other parts of the body in fragile X syndrome, such as accelerated height growth from unrestrained activity in the bones’ stem cells or mental problems caused by excess neurons.

He also notes that basic biological research into fragile X syndrome’s non-neurological symptoms is important since these effects are understudied—and therefore undertreated—compared to problems with mental development.

‘Cars without brakes’

Fragile X syndrome is caused by an error in a single gene in the X chromosome called FMR1. Typically, the FMR1 gene creates a protein called FMRP. In individuals with fragile X syndrome, an abnormality in this gene causes the body to “silence” the production of FMRP.

The researchers found that the absence of FMRP causes a higher rate of cellular growth—driven by symmetric stem cell division. Typically, this process is balanced by asymmetric stem cell division, when old cells are replaced with new ones.

“The cells that lacked FMRP acted like cars without brakes,” says senior author Nicholas Sokol, an associate professor of biology. “They were ready to divide more often and more quickly, and they tended to divide symmetrically, causing the intestine to be bigger than normal.”

The discovery grew from the researchers’ earlier research into another gene, called LIN-28, that also appeared to affect growth in the intestinal cells in fruit flies. During that study, researchers came across evidence that FMRP—the protein encoded by the gene that causes fragile X syndrome—played a role in the same biomolecular pathway as LIN-28.

The earlier study found that lower levels of LIN-28 reduced insulin receptors in the intestines. The reduced number of insulin receptors slowed cellular growth.

Treatment for Fragile X could target this protein

The new study found that stem cells from the intestines of flies whose genes contained the genetic mutation for fragile X syndrome activated these insulin receptors at a higher rate than normal cells.

Moreover, scientists found that higher levels of FMRP affected LIN-28 levels, but not vice versa, suggesting that FMRP plays a controlling role in the biological pathway.

Opening doors

The research may also open doors to research on new treatments of fragile X syndrome, Luhur says. For example, the study found that reducing the insulin-signaling activity in fruit flies’ intestines using genetic interventions or changes in nutrition could restore normal cell growth.

The connection between insulin receptor activity and intestinal growth may also provide new insight into other research, which has shown that the FDA-approved diabetes drug Metformin seems to alleviate some of the neurological symptoms of fragile X syndrome.

“The next step is conducting additional research on FMR1 and LIN-28 in animals to learn more about their biochemical relationship and their effect on metabolism in the body,” Luhur says. “These are important questions for understanding how their interaction affects physiology and human health.”

How to reduce subtle symptoms of fragile X

Researchers report their findings in the journal Cell Reports. The National Institutes of Health supported the work.

Source: Indiana University

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