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Open Access Research article

The absence of dystrophin brain isoform expression in healthy human heart ventricles explains the pathogenesis of 5' X-linked dilated cardiomyopathy

Marcella Neri1, Emanuele Valli2, Giovanna Alfano3, Matteo Bovolenta1, Pietro Spitali1, Claudio Rapezzi4, Francesco Muntoni5, Sandro Banfi3, Giovanni Perini2, Francesca Gualandi1 and Alessandra Ferlini1*

Author Affiliations

1 Department of Experimental Diagnostic Medicine, Section of Medical Genetics, University of Ferrara, Ferrara, Italy

2 Department of Biology, University of Bologna, Bologna, Italy

3 Telethon Institute of Genetics and Medicine, Naples, Italy

4 Institute of Cardiology, University of Bologna and S. Orsola Malpighi Hospital, Bologna, Italy

5 Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London, UK

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BMC Medical Genetics 2012, 13:20  doi:10.1186/1471-2350-13-20

Published: 28 March 2012

Abstract

Background

In 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.

Methods

We 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.

Results

Unlike 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.

Conclusions

The 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.