Identification of microRNAs associated with human fragile X syndrome using next-generation sequencing

Abstract

Fragile X syndrome (FXS) is caused by a mutation in the FMR1 gene which can lead to a loss or shortage of the FMR1 protein. This protein interacts with specific miRNAs and can cause a range of neurological disorders. Therefore, miRNAs could act as a novel class of biomarkers for common CNS diseases. This study aimed to test this theory by exploring the expression profiles of various miRNAs in Iranian using deep sequencing-based technologies and validating the miRNAs affecting the expression of the FMR1 gene. Blood samples were taken from 15 patients with FXS (9 males, 6 females) and 12 controls. 25 miRNAs were differentially expressed in individuals with FXS compared to controls. Levels of 9 miRNAs were found to be significantly changed (3 upregulated and 6 downregulated). In Patients, the levels of hsa-miR-532-5p, hsa-miR-652-3p and hsa-miR-4797-3p were significantly upregulated while levels of hsa-miR-191-5p, hsa-miR-181-5p, hsa-miR-26a-5p, hsa-miR-30e-5p, hsa-miR-186-5p, and hsa-miR-4797-5p exhibited significant downregulation; and these dysregulations were confirmed by RT‐qPCR. This study presents among the first evidence of altered miRNA expression in blood samples from patients with FXS, which could be used for diagnostic, prognostic, and treatment purposes. Larger studies are required to confirm these preliminary results.

Growth-suppressor microRNAs mediate synaptic overgrowth and behavioral deficits in Fragile X mental retardation protein deficiency

“…A miRNA expression profiling study in a small cohort in China noted decreases in several mature let-7 miRNA family members, including let-7a, d, and f, in blood samples from children (mean age 4–5 years) diagnosed with ASD compared to age-matched controls. 155 The let-7 miRNAs were not amongst the miRNAs selected for further evaluation in a recent small size clinical report (15 patients, 12 control subjects) surveying miRNA levels in erythrocytes 156 ; conclusions are restricted by the limited data presented and the mixing of premutation, mosaic, and ‘full’ mutation FXS patients along with characteristics of sex, age (25–80 years), and comorbidity for seizures and for attention deficit hyperactivity disorder, characteristics which were also not matched with control subjects. Differential miRNA expression patterns in postmortem brain tissue from a range of adults diagnosed with ASD also revealed collective and concerted changes in mature let-7 family miRNAs, as compared to controls 157 ; let-7 miRNAs appeared collectively increased in these ASD patient samples.…”

The interplay between miRNAs and chromatin regulators underpins premature differentiation within neurodevelopmental disorders (NDDs)

“…Alongside HMTs, another set of key epigenetic regulators are microRNAs, small non-coding RNAs capable of targeting at least 60% of protein coding genes within the human genome [19]. MircoRNAs are essential regulators of every stage of brain development and maturation, with deregulation of miRNAs associated with NDDs including Autism, Fragile X syndrome and Schizophrenia [20][21][22]. Having two mechanisms of inhibition, mRNA decay and translational repression, it has often been argued that the larger fluctuations in mRNA levels indicate that mRNA degradation is the principal effect of miRNA repression [23,24].…”