ArticleBMC medical genetics2012
The absence of dystrophin brain isoform expression in healthy human heart ventricles explains the pathogenesis of 5' X-linked dilated cardiomyopathy.
Article in BMC medical genetics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 19 citations in OpenAlex.
- The multifaceted view of heart problem in Duchenne muscular dystrophy.Cellular and molecular life sciences : CMLS · 2021Review
- Causes of clinical variability in Duchenne and Becker muscular dystrophies and implications for exon skipping therapies.Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology · 2020Article
- Duchenne Muscular Dystrophy: the Heart of the Matter.Current heart failure reports · 2020Review
- The Genetic Landscape of Dystrophin Mutations in Italy: A Nationwide Study.Frontiers in genetics · 2020Article
- X-Linked Dilated Cardiomyopathy: A Cardiospecific Phenotype of Dystrophinopathy.Pharmaceuticals (Basel, Switzerland) · 2015Review
- Treatment of dystrophin cardiomyopathies.Nature reviews. Cardiology · 2014Review
- Exclusive skeletal muscle correction does not modulate dystrophic heart disease in the aged mdx model of Duchenne cardiomyopathy.Human molecular genetics · 2013Article
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Authors and funding
11 authors at 5 institutions in 2 countries.
Funding
Abstract
backgroundIn X-linked dilated cardiomyopathy due to dystrophin mutations which abolish the expression of the M isoform (5'-XLDC), the skeletal muscle is spared through the up-regulation of the Brain (B) isoform, a compensatory mechanism that does not appear to occur in the heart of affected individuals.
methodsWe quantitatively studied the expression topography of both B and M isoforms in various human heart regions through in-situ RNA hybridization, Reverse-Transcriptase and Real-Time PCR experiments. We also investigated the methylation profile of the B promoter region in the heart and quantified the B isoform up regulation in the skeletal muscle of two 5'-XLDC patients.
resultsUnlike the M isoform, consistently detectable in all the heart regions, the B isoform was selectively expressed in atrial cardiomyocytes, but absent in ventricles and in conduction system structures. Although the level of B isoform messenger in the skeletal muscle of 5'-XLDC patients was lower that of the M messenger present in control muscle, it seems sufficient to avoid an overt muscle pathology. This result is consistent with the protein level in XLDC patients muscles we previously quantified. Methylation studies revealed that the B promoter shows an overall low level of methylation at the CG dinucleotides in both atria and ventricles, suggesting a methylation-independent regulation of the B promoter activity.
conclusionsThe ventricular dilatation seen in 5'-XLDC patients appears to be functionally related to loss of the M isoform, the only isoform transcribed in human ventricles; in contrast, the B isoform is well expressed in heart but confined to the atria. Since the B isoform can functionally replace the M isoform in the skeletal muscle, its expression in the heart could potentially exert the same rescue function. Methylation status does not seem to play a role in the differential B promoter activity in atria and ventricles, which may be governed by other regulatory mechanisms. If these mechanisms could be deduced, de-silencing of the B isoform may represent a therapeutic strategy in 5'-XLDC patients.
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