Abstract
Cardiac involvement is one of the most important manifestations of the multisystemic phenotype of patients affected by myotonic dystrophy (DM) and represents the second cause of premature death. Molecular mechanisms responsible for DM cardiac defects are still unclear; however, missplicing of the cardiac isoform of troponin T (TNNT2) and of the cardiac sodium channel (SCN5A) genes might contribute to the reduced myocardial function and conduction abnormalities seen in DM patients. Since, in DM skeletal muscle, the TNNT2 gene shows the same aberrant splicing pattern observed in cardiac muscle, the principal aim of this work was to verify if the TNNT2 aberrant fetal isoform expression could be secondary to myopathic changes or could reflect the DM cardiac phenotype. Analysis of alternative splicing of TNNT2 and of several genes involved in DM pathology has been performed on muscle biopsies from patients affected by DM type 1 (DM1) or type 2 (DM2) with or without cardiac involvement. Our analysis shows that missplicing of muscle-specific genes is higher in DM1 and DM2 than in regenerating control muscles, indicating that these missplicing could be effectively important in DM skeletal muscle pathology. When considering the TNNT2 gene, missplicing appears to be more evident in DM1 than in DM2 muscles since, in DM2, the TNNT2 fetal isoform appears to be less expressed than the adult isoform. This evidence does not seem to be related to less severe muscle histopathological alterations that appear to be similar in DM1 and DM2 muscles. These results seem to indicate that the more severe TNNT2 missplicing observed in DM1 could not be related only to myopathic changes but could reflect the more severe general phenotype compared to DM2, including cardiac problems that appear to be more severe and frequent in DM1 than in DM2 patients. Moreover, TNNT2 missplicing significantly correlates with the QRS cardiac parameter in DM1 but not in DM2 patients, indicating that this splicing event has good potential to function as a biomarker of DM1 severity and it should be considered in pharmacological clinical trials to monitor the possible effects of different therapeutic approaches on skeletal muscle tissues.
Highlights
Myotonic dystrophy type 1 (DM1; OMIM#160900) and type 2 (DM2; OMIM#602668) are dominantly inherited neuromuscular disorders characterized by a multisystemic involvement including muscle weakness, myotonia, respiratory insufficiency, central nervous system impairment, conduction system disease, ventricular dysfunction, and supraventricular and ventricular arrhythmias [1]
DM type 1 (DM1) is caused by an expanded CTG repeat in the 3′ untranslated region (UTR) of the Dystrophia Myotonic Protein Kinase gene (DMPK) [2,3,4], while DM2 is caused by expanded CCTG repeats in intron 1 of the CCHC-type zinc finger, Nucleic acid Binding Protein gene (CNBP/ZNF9) [5]
The DM1 cohort was represented by patients affected by the mild form or by the classical adult form of the disease; the DM2 cohort was represented by patients with classical Proximal Myotonic Myopathy (PROMM) phenotype
Summary
Myotonic dystrophy type 1 (DM1; OMIM#160900) and type 2 (DM2; OMIM#602668) are dominantly inherited neuromuscular disorders characterized by a multisystemic involvement including muscle weakness, myotonia, respiratory insufficiency, central nervous system impairment, conduction system disease, ventricular dysfunction, and supraventricular and ventricular arrhythmias [1]. Regulation of alternative splicing of exon 5 leads to exon inclusion in mRNAs produced during early development of heart and skeletal muscle and to exon exclusion in adult heart [28]. These two TNNT2 isoforms confer different calcium sensitivity to the myofilament, affecting the contractile properties of maturing muscle [29, 30]. Adult cardiac muscle of DM patients shows alteration of TNNT2 alternative splicing such that inclusion of exon 5 is inappropriately increased; the expression of this fetal isoform in DM1 patients’ heart might contribute to the reduced myocardial function and conduction abnormalities seen in these patients [25]
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