Urine microRNA Is Potential Biomarker for Fragile X, Early Study Suggests

A small RNA molecule detectable in urine, called miR-125a, may provide a new biomarker for fragile X syndrome that could be used to group patients based on individual differences in brain pathways, an early study suggests.

The study, “Urine microRNA Profiling Displays miR-125a Dysregulation in Children with Fragile X Syndrome,” was published in the journal Cells.

Fragile X, a common cause of inherited intellectual disability and autism, is caused by a mutation in which a DNA segment, known as the CGG triplet, is expanded within the FMR1 gene. (C stands for cytosine and G for guanine, two of the four building blocks of DNA).

Normally, this DNA segment is repeated from five to 55 times, but in people with fragile X it is repeated more than 200 times; that is known as a “full” mutation.  Some people have a premutation and carry a CGG segment of intermediate size, with 55–200 of such repeats.

Full mutations turn off (silence) the FMR1 gene, which prevents the gene from producing the fragile X mental retardation 1 protein (FMRP). This protein is present in many tissues, but it is believed to play an important role in the functioning of nerve cells, or neurons, and their communication. As such, loss or shortage of FMRP disrupts nervous system functions leading to fragile X.

Premutation carriers do not have fragile X, but are at risk for having an adult-onset neurodegenerative disorder called fragile X tremor-ataxia syndrome (FXTAS).

Disease severity and response to treatments vary considerably among those with fragile X. This requires personalized treatment approaches and makes it difficult to conduct clinical trials.

MicroRNAs (miRNAs) are short RNA molecules that affect the expression or activity of genes. Many miRNAs have been involved in the development of several disorders, including neurological diseases. Disruption of miRNA appears to contribute to fragile X development by impairing the communication between nerve cells.

In a bid to identify miRNA biomarkers of fragile X, researchers at the University of Helsinki, in Finland, and their collaborators compared the levels of miRNAs in the urine of a boy with this disorder and his twin brother, who was a premutation carrier and had no clinical signs of fragile X

Using next-generation sequencing, the team identified 28 miRNAs whose levels were different between the two twins. Among the eight miRNAs with higher levels in the brother with fragile X, the largest difference was found in the levels of a miRNA known as miR-125a — a 1.6-fold increase compared to his twin brother.

The overabundance of miR-125a was confirmed by additional methods. In addition, it also was seen in two other sets of urine samples from children and teens with fragile X (ages 2–17, nine Finnish and 10 Spanish patients), compared to healthy subjects.

Urine miR-125a levels appeared to increase with age in healthy individuals, but to vary widely in young fragile X patients.

The variable levels in the fragile X group suggest that, should the results be generalized, two subgroups might exist. Patients with low levels of miR-125a in urine may differ in terms of cellular alterations from the group with higher levels of miR-125a, the researchers said.

miRNAs altered in fragile X were predicted to play roles in developmental processes, homeostasis (self-regulation and stabilization of bodily states), and nerve cell function.

miR-125a has been associated with the signals relayed by type I metabotropic glutamate receptor (mGluR1 and mGluR5), a key “hub” molecule that regulates nerve cell communication and implicated in neurological disorders. This type of receptors, as well as the signals they send, actually have been proposed as treatment targets for fragile X, the scientists said.

“[U]rine miR-125a levels may provide a novel tool to subgroup FXS children based on individual differences linked particularly to mGluR5 signaling, which is considered to be the most critically dysregulated signaling pathway in FXS [fragile X syndrome],” the researchers wrote.

The results “provide evidence that urine miR-125a could be a potential novel biomarker in FXS clinical trials,” they added, although larger studies are necessary to confirm the findings and explore the impact of other miRNAs.