Circulating microRNAs in Fabry Disease

Abstract

Fabry disease is an X-linked deficiency of the lysosomal hydrolase alpha-galactosidase A (alpha-Gal).This results in an accumulation of globotriaosylceramide (GL-3/Gb3) in a variety of cells with subsequent functional impairment. The continuous progress of FD often leads to decreased quality of life and premature death caused by multi-organic complications. The overall aim of our study was to determine the amount of circulating miRNAs in Fabry patients and to test whether ERT would alter the level of individual circulating miRNAs. We used miRNA sequencing by the HTG EdgeSeq System to identify the circulating miRNA pool from Fabry patients with and without enzyme replacement therapy (n = 6). In total, 296 miRNAs in serum of patients were identified. Among them 9 miRNAs were further evaluated in extra serum samples (n = 31) using real-time qPCR and 6 of them showed significant differential expression. The resulting miRNA pattern may help to better understand mechanisms involved in the beneficial effects of ERT and these new miRNA markers could help to estimate the efficacy of ERT or to identify Fabry patients with specific need for ERT.Fabry disease (FD) is an X-chromosome linked disorder caused by mutations in gene GLA coding for alpha-galactosidase-A enzyme (alpha-Gal). The enzyme activity deficiency that results in an accumulation of globotriaosylceramide (GL-3/Gb3) in a variety of cells often leads to subsequent functional impairment 1 . The initial manifestations of Fabry disease usually start in adolescence stage of life, including neuropathic pain (acroparesthesia) and abdominal discomfort 2 . The continuous progress of FD results in decreased quality of life and premature death caused by multi-organic complications 3,4 . As a specific treatment, Enzyme replacement therapy (ERT) has been shown to stabilize and reduce many signs and symptoms of Fabry disease 5-7 . More recently, oral chaperone therapy was shown to be also effective in selected Fabry patients depending on the underlying gene mutation 8 . Of clinical importance is the fact that early diagnosis and treatment in the disease course may delay or prevent the progression towards irreversible organ dysfunction and the consequent life-threatening complications. This is sometimes difficult due to the high variability of the severity and multi-organ system involvement in Fabry disease 9 . Next to the clinical features, enzyme activity tests and DNA sequencing are available to confirm the diagnosis 10 . Globotriaosylsphingosine (LysoGb3) serves as a useful biomarker to improve the diagnosis of heterozygous Fabry disease for therapeutic evaluation and monitoring 11 . In addition, circulating serum proteins in the blood of Fabry patients may help to get more information about the underlying pathophysiological mechanisms 12 .Recently, a group of small RNA molecules known as microRNAs (miRNAs) have been proved to play essential roles in the cardiac function 13,14 . Moreover, the expression levels of miRNAs that present in circulating fluid usually differ betw...

Non-Coding RNAs in Hereditary Kidney Disorders

“…The circulating miR199a-5p and miR-126-3p are upregulated in Fabry patients, which can be normalized in Fabry patients after ERT [ 118 ]. To further determine whether ERT alters the level of circulating miRNAs in Fabry patients, Xiao et al performed the microRNA sequencing for the serum samples from Fabry patients with or without ERT [ 119 ]. A total of 145 miRNAs are identified to be regulated by ERT.…”

“…A total of 145 miRNAs are identified to be regulated by ERT. Among those miRNAs, miR-1307-5p, miR-21-5p, miR-152-5p and miR-26a-5p were confirmed to be downregulated in the serum of Fabry patients after ERT in a validation cohort [ 119 ]. These studies suggested that urinary and circulating miRNAs might be used as biomarkers to assess the disease progression and the efficacy of ERT in Fabry patients.…”

Biomarkers of Fabry Nephropathy: Review and Future Perspective

“…In serum, specific miRNAs species, namely, miR-1307-5p, miR-21-5p, miR-152-5p, and miR-26a-5p, were significantly down-regulated in Fabry patients with ERT, compared to those without. Additionally, miR-19a-3p and miR-486-5p were reported to be down-regulated only in male patients with ERT [82]. The analysis of miRNA expression is not commonly used in the clinical practice, due to the lack of standardized protocols.…”

Biomarkers in Anderson–Fabry Disease

“…The pathways that were investigated were axon guidance signalling pathways and the TGF-beta signalling pathway, which were found to be targets of miRNAs. It was reported that abnormal regulation of miRNAs resulted in changes in axon guidance pathways: this effect may contribute to neurological processes leading to neurological manifestations in Fabry disease [79].…”