Circulating miR-323-3p is a biomarker for cardiomyopathy and an indicator of phenotypic variability in Friedreich\u2019s ataxia patients

M Seco-Cervera,J L García-Giménez,J S Ibáñez-Cabellos,F V Pallardó,D González-Rodríguez,I Sanz-Gallego,E García-López,J J Vílchez,L Peiró-Chova,P González-Cabo

doi:10.1038/s41598-017-04996-9

Abstract

MicroRNAs (miRNAs) are noncoding RNAs that contribute to gene expression modulation by regulating important cellular pathways. In this study, we used small RNA sequencing to identify a series of circulating miRNAs in blood samples taken from Friedreich’s ataxia patients. We were thus able to develop a miRNA biomarker signature to differentiate Friedreich’s ataxia (FRDA) patients from healthy people. Most research on FDRA has focused on understanding the role of frataxin in the mitochondria, and a whole molecular view of pathological pathways underlying FRDA therefore remains to be elucidated. We found seven differentially expressed miRNAs, and we propose that these miRNAs represent key mechanisms in the modulation of several signalling pathways that regulate the physiopathology of FRDA. If this is the case, miRNAs can be used to characterize phenotypic variation in FRDA and stratify patients’ risk of cardiomyopathy. In this study, we identify miR-323-3p as a candidate marker for phenotypic differentiation in FRDA patients suffering from cardiomyopathy. We propose the use of dynamic miRNAs as biomarkers for phenotypic characterization and prognosis of FRDA.

Highlights

Friedreich’s ataxia (FRDA), an autosomal recessive neurodegenerative mitochondrial disease, is the most prevalent hereditary ataxia in people of European descent, affecting around 2–5 people in every 100,000 (Orphanet reports)
We have previously demonstrated the relationship between antioxidant cellular response, energy metabolism and mitochondrial signalling in fibroblasts from FRDA patients, highlighting the possible role of different metabolic sensors (AMPK, p38, PGC-1α and mtTFA) in mitochondrial dysfunction and characterizing the role of new metabolic pathways involved in the pathophysiology of FRDA17
Twenty-five Caucasian FRDA patients from different families were enrolled in this study, all of whom had their diagnosis confirmed by genetic testing

Summary

Introduction

Friedreich’s ataxia (FRDA), an autosomal recessive neurodegenerative mitochondrial disease, is the most prevalent hereditary ataxia in people of European descent, affecting around 2–5 people in every 100,000 (Orphanet reports). This rare, childhood-onset disease is characterized by a progressive loss of sensory neurons in the dorsal root ganglia (DRG) and posterior columns. FRDA is most often caused by a homozygous GAA repeat expansion mutation (typically between 600 and 1200 repeats) in the first intron of the frataxin gene (FXN), which is found on chromosome 9q21.11 and encodes the protein frataxin[2, 9]. 10) have been proposed as causes of decreased expression of the mitochondrial protein frataxin[11]. MiRNAs participate in the regulation of frataxin levels[18, 19]

Methods

Results

Conclusion