Long Noncoding RNAs May Be New Target for Diagnosis, Treatment of Fragile X Spectrum Disorders

Long noncoding RNAs (lncRNAs) — long RNA molecules that do not provide instructions to make proteins and are thought to be involved in gene regulation — may become a new target for diagnosing and treating patients with fragile X spectrum disorders, according to a recent review.

The review study, “Long Noncoding RNA Can Be a Probable Mechanism and a Novel Target for Diagnosis and Therapy in Fragile X Syndrome,” was published in Frontiers in Genetics.

Fragile X syndrome (FXS) is the most frequent single genetic cause of autism spectrum disorder (ASD). Fragile X is caused by the expansion of CGG repeats in the fragile X mental retardation 1 (FMR1) gene, which provides instructions for making a protein called fragile X mental retardation protein (FMRP).

Unlike individuals carrying the full mutation (those who have more than 200 CGG repeats), premutation carriers (those who have 55 to 200 CGG repeats) usually maintain their intellectual abilities. These include, for instance, patients with fragile X-associated primary ovarian insufficiency (FXPOI), a condition that compromises women’s ovary function, and fragile X-associated tremor/ataxia syndrome (FXTAS), a condition that mostly affects older patients and is characterized by motor and cognitive impairments.

“Previous studies have recently indicated that lncRNAs contribute to the pathogenesis [disease manifestations] of both the full mutation and premutation carriers, especially in nervous disorders. Still, there is no summary of function and mechanism of lncRNAs in [fragile X] patients and premutation carriers,” the investigators wrote.

This review study focused on gathering and summarizing the main findings of studies assessing the role of lncRNAs in fragile X, FXTAS and FXPOI, as well as providing an outlook on future applications these lncRNAs may have on the diagnosis and treatment of these genetic disorders.

Previous studies have shown there are several lncRNAs that derive from the same region encoding the FMR1 gene in fragile X full mutation carriers and FXTAS/FXPOI premutation carriers. These include, for instance, FMR4, FMR5, and FMR6.

FMR4 is encoded (originated) by a sequence located upstream of the FMR1 gene and has been found in both healthy individuals and premutation carriers, but not in fragile X patients. It seems to play a role in controlling gene expression during differentiation of neural precursor cells (cells that are able to grow into all types of nerve cells in the body) in humans. Of note, gene expression is the process by which information in a gene is synthesized to create a working product, like a protein.

“Similar to FMR1 mRNA [messenger RNA, the template for the production of a protein] level, the expression of FMR4 is up-regulated in premutation carriers and silenced in brain tissue of full mutation carriers (fragile X). Some previous research has shown that overexpression and knockdown of FMR4 can alter the expression of these genes, which has an effect on cellular proliferation or differentiation,” the researchers wrote.

Like FMR4, FMR5 also is encoded by a sequence upstream of the FMR1 gene, and it has been found in brain tissue from healthy individuals, premutation and full mutation carriers.

FMR6 is a lncRNA whose sequence is partially complementary to that of the FMR1 mRNA. Its expression levels have been found to be down-regulated in brain tissue from premutation and full mutation carriers. Some studies suggest that FMR6 is likely involved in the onset of FXPOI, and may regulate the production and stability of FMR1 mRNA.

“For [fragile X] and FXTAS/FXPOI patients, it is feasible that the levels of these transcripts (FMR6, FMR5, FMR4 and FMR1) can correspond to different clinical manifestations and results. Therefore, these lncRNAs may be taken for markers to diagnose and evaluate [fragile X] and FXTAS/FXPOI,” the investigators explained.

“By understanding the mystery of these lncRNAs, the diagnosis and treatment of [fragile X], along with its associated disorders, may be more accurate and effective in the future,” they added.