Elsevier

Neuromuscular Disorders

Volume 9, Issue 5, 1 July 1999, Pages 339-346
Neuromuscular Disorders

X-linked dilated cardiomyopathy and the dystrophin gene

https://doi.org/10.1016/S0960-8966(99)00015-2Get rights and content

Abstract

X-linked dilated cardiomyopathy (XLDC) represents a well known genetic disease, allelic to Duchenne and Becker muscular dystrophies and caused by dystrophin gene mutations. XLDC is a rare disease and only few families have been fully characterised. In several of them, the dystrophin mutations show a different pattern of expression in cardiac compared to skeletal muscle. In the families with the most severe cardiac phenotype, the cardiac muscle is usually unable to produce dystrophin, due to a specific effect that the mutation(s) have on the gene transcription in this tissue. The skeletal muscle escapes the dystrophic changes by maintaining dystrophin synthesis via exon skipping or alternative splicing that the heart is not able to put in place. In this paper we have reviewed the families with X-linked dilated cardiomyopathy reported so far; in addition we provided novel transcription data on two families we previously described. The aim of this review is to attempt a genotype-phenotype correlation and speculate on common pathogenic mechanisms underlying this disease.

Introduction

X-linked dilated cardiomyopathy (XLDC) belongs to the genetically heterogeneous group of the dilated cardiomyopathies (DC) and it has been demonstrated to be an allelic disorder to Duchenne and Becker muscular dystrophies (DMD or BMD) [1]. In contrast to DMD and BMD, the only symptom in patients with XLDC is related to the cardiac phenotype; however, elevated serum CK is almost invariably found in affected individuals and the skeletal muscle biopsy shows myopathic changes [2].

Two types of dystrophin mutations have been identified so far in several XLDC families: (i) mutations similar to those found in patients with typical DMD or BMD phenotype; (ii) unusual gene defects not found in patients with typical DMD or BMD 3, 4, 5, 6, 7, 8, 9, 10, 11. Due to the heterogeneity of the dystrophin mutations identified so far, the pathogenesis underlying the selective cardiac muscle impairment in the XLDC families represents a fascinating puzzle. Although some potential correlation between genotype and phenotype have emerged, the precise relationship between dystrophin mutations and cardiomyopathy is still not entirely clear.

Two main regions of the dystrophin gene appeared to be most commonly involved in XLDC: the 5′ end of the gene, and the central hot-spot region, centred around exons 48–49.

Several families with XLDC have been found to have mutations in this region. Rearrangements in the muscle promoter (M) and adjacent intron 1 have been described in three unrelated families with XLDC 3, 9. A point mutation abolishing the canonical 3′ splice site of M exon 1 has also been reported in another family [5]. These mutations have in common the loss of the full length M isoform expression in the heart 12, 13, 14, 15.

Two other 5′ end mutations were recently reported in XLDC families. In one family described by Bies [7]the mutation consisted of a duplication involving exons 2–7. The propositus showed a normal amount of dystrophin transcript both in the heart and in the skeletal muscle, but a complete lack of dystrophin protein in the cardiac muscle. The authors hypothesised that the mutation breakpoints could have involved regulatory regions located in the 5′ end of the gene, the absence of which could have caused a down-regulation of the dystrophin transcription and expression in the heart only.

A recently reported unusual mutation is caused by an Alu-like mobile element insertion in intron 11 of the dystrophin gene [11]. We have found that this rearrangement affected the canonical splicing of exons 11 and 12 in the heart, abolishing the normal transcript in the cardiac muscle only. This resulted in absent dystrophin production in the cardiac muscle, while in the skeletal muscle there was a significant residual expression of the protein as a result of the correct splicing of exons 11 and 12.

Another splicing mutation has been reported by Franz [4]. A nonsense mutation in exon 29 caused the exon 29 skipping both in the cardiac and skeletal muscle. The dystrophin protein was however apparently expressed in similar amounts in the two tissues [16].

Although in-frame mutations of this region of the dystrophin gene typically give rise to BMD, rare patients affected by XLDC have been reported carrying in-frame deletions of exons 49–51 [8], 48–49 [8], and 48 in two unrelated patients [10]. Although parallel expression studies in the cardiac and skeletal muscle have not been possible in any of these individuals, one case (carrying a deletion of exons 49–51) showed almost normal levels of a truncated protein in the heart [8].

Finally, Ortiz-Lopez [6]reported a missense mutation in the hinge 1 region of exon 9 in a patient with XLDC. The authors concluded that the epitope encoded by exon 9 must have a specific role in the heart.

The findings of different mutations and different protein expression in all these cases suggest the presence of multiple pathogenic mechanisms to account for the isolated or predominant cardiac involvement in XLDC cases.

In this article we report additional transcription results on two unrelated XLDC patients in which genomic studies have been recently described 10, 11. In addition, with the aim of identifying possible common factors, we have reviewed the published XLDC families for which mutation analysis was available.

Section snippets

Clinical findings

The main clinical findings in the XLDC families reviewed in this article are summarised in Table 1.

Immunocytochemistry

Tissue samples were mounted in OCT and frozen in isopentane cooled in liquid nitrogen. Unfixed frozen sections (6-10m) of hearts and skeletal muscle were cut at −25°C and incubated with primary antibodies for 30 min at room temperature. Following washes in PBS, sections were incubated with biotynilated secondary anti-mouse or anti-rabbit antibodies (Amersham, UK, 1:200) for 30 min at room

Immunocytochemical studies

Cardiac biopsy from patient 7 [11]was immunolabelled with antibodies to (a) N-terminal dystrophin (Dys1), (b) α-sarcoglycan, (c) utrophin, (d) laminin α2 chain. We found absence of dystrophin (bright dots are autofluorescent lipofuscin), reduced expression of α-sarcoglycan, over-expression of utrophin, but normal expression of the laminin α2 chain at the sarcolemma (Fig. 1). We also found that laminin α2 chain was prominent on the T-tubules as well as the sarcolemma but there was almost no

Discussion

In this article we reviewed the dystrophin gene mutations reported in cases of XLDC; although the mutations are heterogeneous, their final common pathway is to give rise to an isolated cardiac phenotype. It is difficult to draw general conclusions from the data available, also because detailed parallel protein and transcription analyses in skeletal and cardiac muscle are only available in a few cases. On the basis of the data available we have attempted to perform a genotype/phenotype

Conclusion

From these data it emerges that different pathogenic mechanisms might be involved in XLDC.

Splicing appears to play a relevant role in the 5′ end mutations. A common problem in these families is the difference in splicing regulation in heart and skeletal muscle; this can explain the isolated heart involvement observed in them.

The pathogenesis of the isolated cardiac phenotype of patients with mutations in the spectrin-like domain is not entirely clear. However, there are some indirect clues that

Acknowledgements

This work is generously financed by the British Heart Foundation (BHF) of Great Britain. Thanks are also due to the `Legato Ferrari' Foundation, Modena (Italy).

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