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Comparative Study
. 2013 Feb 1;111(3):400-5.
doi: 10.1016/j.amjcard.2012.10.017. Epub 2012 Nov 17.

Desmin mutations and arrhythmogenic right ventricular cardiomyopathy

Alessandra Lorenzon  1 , Giorgia Beffagna, Barbara Bauce, Marzia De Bortoli, Ilena E A Li Mura, Martina Calore, Emanuela Dazzo, Cristina Basso, Andrea Nava, Gaetano Thiene, Alessandra Rampazzo
Affiliations
Comparative Study

Desmin mutations and arrhythmogenic right ventricular cardiomyopathy

Alessandra Lorenzon et al. Am J Cardiol. .

Abstract

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease characterized by fibrofatty replacement of the myocardium and ventricular arrhythmias, associated with mutations in the desmosomal genes. Only a missense mutation in the DES gene coding for desmin, the intermediate filament protein expressed by cardiac and skeletal muscle cells, has been recently associated with ARVC. We screened 91 ARVC index cases (53 negative for mutations in desmosomal genes and an additional 38 carrying desmosomal gene mutations) for DES mutations. Two rare missense variants were identified. The heterozygous p.K241E substitution was detected in 1 patient affected with a severe form of ARVC who also carried the p.T816RfsX10 mutation in plakophilin-2 gene. This DES substitution, showing an allele frequency of <0.01 in the control population, is predicted to cause an intolerant amino acid change in a highly conserved protein domain. Thus, it can be considered a rare variant with a possible modifier effect on the phenotypic expression of the concomitant mutation. The previously known p.A213V substitution was identified in 1 patient with ARVC who was negative for mutations in the desmosomal genes. Because a greater prevalence of p.A213V has been reported in patients with heart dilation than in control subjects, the hypothesis that this rare variant could have an unfavorable effect on cardiac remodeling cannot be ruled out. In conclusion, our data help to establish that, in the absence of skeletal muscle involvement suggestive of a desminopathy, the probability of DES mutations in ARVC is very low. These findings have important implications in the mutation screening strategy for patients with ARVC.

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Figures

Figure 1
Figure 1
DES variants identified in patients with ARVC. (Top) Sequence electropherograms showing p.A213V and p.K241E amino acid substitutions and intronic nucleotide change c.736-11A>G detected in DES gene. (Bottom) ClustalW (European Molecular Biology Laboratory–European Bioinformatics Institute, Cambridgeshire, United Kingdom) alignment showing evolutionary conservation of highly conserved 1B desmin subdomain among species. Organism names and Genbank Accession numbers are reported on the sides (Cf = Canis familiaris; Dr = Danio rerio; Gg = Gallus gallus; Hs = Homo sapiens; Mm = Mus musculus; Rn = Rattus norvegicus; Ss = Sus scrofa; Xl = Xenopus laevis).
Figure 2
Figure 2
Pedigree of patient with ARVC carrying DES p.K241E rare variant. Index patient indicated by arrow. Black, white, and gray symbols represent clinically affected subjects, unaffected subjects, and subjects with unknown disease status, respectively. Presence (asterisk) or absence (−) of gene variations shown.
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