Circular RNAs (
circRNAs) constitute a recently re-discovered class of non-coding RNAs functioning as sponges for
miRNAs and
proteins, affecting RNA splicing and regulating transcription.
CircRNAs are generated by "back-splicing", which is the linking covalently of 3'- and 5'-ends of exons. Thus,
circRNA levels might be deregulated in conditions associated with altered RNA-splicing. Significantly, growing evidence indicates their role in human diseases. Specifically,
myotonic dystrophy type 1 (DM1) is a multisystemic disorder caused by expanded CTG repeats in the DMPK gene which results in abnormal
mRNA-splicing. In this investigation,
circRNAs expressed in DM1 skeletal muscles were identified by analyzing
RNA-sequencing data-sets followed by qPCR validation. In muscle biopsies, out of nine tested, four transcripts showed an increased circular fraction: CDYL, HIPK3, RTN4_03, and ZNF609. Their circular fraction values correlated with skeletal muscle strength and with splicing
biomarkers of disease severity, and displayed higher values in more severely affected patients. Moreover, Receiver-Operating-Characteristics curves of these four
circRNAs discriminated DM1 patients from controls. The identified
circRNAs were also detectable in peripheral-blood-mononuclear-cells (PBMCs) and the plasma of DM1 patients, but they were not regulated significantly. Finally, increased circular fractions of RTN4_03 and ZNF609 were also observed in differentiated myogenic cell lines derived from DM1 patients. In conclusion, this pilot study identified
circRNA dysregulation in DM1 patients.