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X-linked dilated cardiomyopathy (XLDC) and the dystrophin gene

(last modified September 11, 2004)

This page was made with the help of Dr. Francesco Muntoni.

Contents

• Definition
• Description
• Mutation table

Definition

X-linked dilated cardiomyopathy (XLDC, sometimes abbreviated as XLDCM) is a clinical phenotype of dystrophinopathy which is characterized by preferential myocardial involvement without any overt signs of skeletal myopathy. It is a familial myocardial disease that presents with lethal congestive heart failure in young males in their teens or early twenties. A significant portion of XLDC-patients carry mutations in the dystrophin gene (Muntoni, Towbin).

X-linked dilated cardiomyopathy (XLDC) entry in OMIM (302045)

Description

Some mutations of the dystrophin gene are mainly or exclusively associated with a cardiac involvement. In addition, other mutations, usually associated with a typical muscular dystrophy (usually BMD), in rare instances can present with dilated cardiomyopathy and fail to show a significant skeletal muscle involvement. The precise correlation between mutations in the dystrophin gene and cardiomyopathy is still not clear. The complexity of this issue is related to the presence of numerous dystrophin isoforms, the rarity of some of the mutations described and the difficulty to perform parallel histological studies of skeletal and cardiac muscle in affected individuals.

Linkage

In 1987, Berko and Swift described a black family in which 11 young males showed dilated cardiomyopathy. Symptoms occurred between ages 15 and 21 years. A diagnosis of definite late-onset dilated cardiomyopathy was given in 3 mothers of affected males presenting, in their forties, with atypical chest pain. Progressive congestive heart failure developed gradually over a period of 10 years or more.

Towbin et al. performed a linkage studies in the large kindred described by Berko and Swift and in a smaller second pedigree. Linkage of XLCM to the centromeric portion of the dystrophin locus was demonstrated, with a combined maximum lod score of 4.33 (at theta = 0.0) using 2-point linkage and 4.81 using multipoint linkage analysis. No deletions could be detected. Abnormalities of cardiac dystrophin were shown by Western blotting with an N-terminal dystrophin antibody, whereas skeletal muscle dystrophin was normal, suggesting primary involvement of the dystrophin gene with cardiac muscle preferentially affected.

Mutations

Regarding the mutations specifically associated with a cardiomyopathy, there is evidence that mutations affecting the extreme 5' end of the dystrophin gene can give rise to isolated dilated cardiomyopathies. Muntoni described a deletion of, and Yoshida (1998) an L1-insertion in the Dp427m promoter / first exon in an XLDC-family. Milasin reported a mutation of the Dp427m promoter / first exon splice site affecting splicing of the muscle-specific transcript. Similar mutations are exceptional in the general BMD / DMD population. XLDC-patients had no detectable muscle weakness, but CPK levels were invariably elevated and muscle histology showed myopathic changes, suggesting that the skeletal muscle was also mildly involved. Patients developed cardiac symptoms in the second decade of life or in the early thirties.

A unique mutation was described by Ferlini et al. (1998) in an extensive XLDC-family of Sardinian descent. Transcription analysis in muscle revealed, next to a normal transcript, a transcript with a 159 bp insertion between exons 11 and 12, introducing an in-frame translational stop. In heart muscle, only the altered transcript was present. The insert was derived from an Alu-like repetitive sequence, located about 2.5 kb downstream of exon 11. The presence of the repetitive sequence at this site was unique for the patient and probably derives from an insertion mutation. Due the intronic constitution, new splice sites are activated (in a tissue-specific way); a cryptic splice acceptor site in dystrophin intron 11 and a splice donor site from the repetitive sequence.

There are a few case reports of patients with a mutation in the 5' or 3' deletion hot spot of the dystrophin gene presenting a dilated cardiomyopathy; deletions of exons 2-7 (Gold [1992]), 2-7 (Nigro [1997]), 3-7 (Nigro [1997]) and exons (5)6-13(14/15) (Oldfors [1994]), were described in patients presenting heart failure. Immunocytochemical analysis of dystrophin in the skeletal and cardiac muscle showed the expression of low abundant dystrophin in both tissues in one of these cases (Nigro [1997]). Patients with a deletion in the 3' hot spot region (exons 48-49 and 49-51) presenting with a dilated cardiomyopathy have also been reported (Piccolo [1994], Gold [1992]. Intriguingly, one of these cases was a 52 year old men with normal CPK-levels, who underwent a cardiac transplant for a dilated cardiomyopathy (Gold [1992]).

Separate mechanisms from the ones outlined above also exist. Ortiz-Lopez (1997) reported a missense mutation in exon 9 in the XLDC-family described by Berko and Swift. The mutation (c.835A>G, see also the dystrophin point mutation database) induced a Threonine to Alanine substitution (p.Thr279Ala), affecting a highly conserved amino acid. The mutation results in a change in polarity in the evolutionary conserved first hinge region of the protein, substituting a beta-sheet for a alpha-helix apparently resulting in destabilisation of the protein (Ortiz-Lopez [1997]). Another interesting family was recently reported in which a repetitive Alu-like sequence was inserted in intron 11 of the dystrophin gene, activating a cryptic splice site selectively in the cardiac muscle (Ferlini et al. [1998]).

A few large families with a X-linked dilated cardiomyopathy, clearly secondary to a dystrophinopathy but without an identifiable dystrophin mutation, have also been reported (Muntoni, personal observation and Franz [1995]).

Dystrophin expression

Muntoni (1995) and Nakamura (1997) reported Dp427m, no Dp427p and minimal Dp427c transcription in control skeletal muscle, while in cardiac muscle both Dp427m and Dp427c are expressed (Muntoni [1995]). Characterisation of the pattern of dystrophin expression in XLDC-cases (Muntoni [1995], Muntoni [1995], Muntoni [1997], Nakamura [1997], Gold [1992], Ferlini et al. [1998], Yoshida [1998]) showed up-regulation of Dp427c and Dp427p in skeletal muscle but not in heart (although total dystrophin expression in muscle was reduced in abundance). In two BMD patients, carrying exon 45-47 and 45-48 deletions, all three transcripts were found to be co-expressed.

Mutation table

Legend:

Location: location of mutation, ex = exon, in = intron. Mutation: type of mutation, del = deletions, ins = insertion, spl = splice site mutation (see also the DMD sequence variation database). DNA/RNA: mutation detected in DNA = DNA, RNA = RNA and DNA. Disease: aBMD = atypical BMD. Reference: publication describing patient. OMIM: OMIM identification number. Fam/Sp: fam = familial case, Sp = Sporadic case.

Dr. Francesco Muntoni works at the Department of Paediatrics & Neonatal Medicine of the Hammersmith Hospital in London (UK) and can be reached at (fax) +44-181-3832473 or
(E-mail) fmuntoni @ rpms.ac.uk

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