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Int J Mol Sci. 2019 Apr 19;20(8). pii: E1938. doi: 10.3390/ijms20081938.

Dysregulation of Circular RNAs in Myotonic Dystrophy Type 1.

Author information

1
Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy. christine.voellenkle@grupposandonato.it.
2
Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy. alessandra.perfetti@grupposandonato.it.
3
Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy. carrara.matt@gmail.com.
4
Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy. paola.fuschi@grupposandonato.it.
5
Laboratory of Muscle Histopathology and Molecular Biology, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy. lauravalentina.renna@grupposandonato.it.
6
Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy. marialucia.longo@grupposandonato.it.
7
Center for Translational Genomics and Bioinformatics, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. baghaisain.simona@hsr.it.
8
Laboratory of Muscle Histopathology and Molecular Biology, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy. rosanna.cardani@grupposandonato.it.
9
Research Laboratories, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy. rea.valaperta@grupposandonato.it.
10
Department of Geriatrics, Orthopaedic and Neuroscience, Institute of Neurology, Catholic University of Sacred Heart, Fondazione Policlinico Gemelli, 00168 Rome, Italy. Gabriella.Silvestri@unicatt.it.
11
Department of Biology and Biotechnology "Charles Darwin", Sapienza University of Rome, 00185 Rome, Italy. Ivano.Legnini@mdc-berlin.de.
12
Department of Biology and Biotechnology "Charles Darwin", Sapienza University of Rome, 00185 Rome, Italy. irene.bozzoni@uniroma1.it.
13
Sorbonne Université, INSERM, Association Institut de Myologie, Centre de Recherche en Myologie, F-75013 Paris, France. denis.furling@upmc.fr.
14
Laboratory of Epigenetics, Istituti Clinici Scientifici Maugeri, 27100 Pavia, Italy. carlo.gaetano@icsmaugeri.it.
15
Institute of Cell Biology and Neurobiology, National Research Council, Monterotondo, 00015 Rome, Italy. germana.falcone@cnr.it.
16
Laboratory of Muscle Histopathology and Molecular Biology, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy. giovanni.meola@unimi.it.
17
Department of Neurology, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy. giovanni.meola@unimi.it.
18
Department of Biomedical Sciences for Health, University of Milan, 20133 Milan, Italy. giovanni.meola@unimi.it.
19
Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy. fabio.martelli@grupposandonato.it.

Abstract

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.

KEYWORDS:

alternative splicing; circular RNA; muscular dystrophies

PMID:
31010208
PMCID:
PMC6515344
DOI:
10.3390/ijms20081938
[Indexed for MEDLINE]
Free PMC Article

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