Novel Desmin Mutation p.Glu401Asp Impairs Filament Formation, Disrupts Cell Membrane Integrity, and Causes Severe Arrhythmogenic Left Ventricular Cardiomyopathy/Dysplasia
Background —Desmin ( DES ) mutations cause severe skeletal and cardiac muscle disease with heterogeneous phenotypes. Recently, DES mutations were described in patients with inherited arrhythmogenic right ventricular cardiomyopathy/dysplasia (iARVC/D), although their cellular and molecular pathomechanisms are not precisely known. Our aim is to describe clinically and functionally the novel DES -p.Glu401Asp mutation as a cause of inherited left ventricular arrhythmogenic cardiomyopathy/dysplasia (iLVAC/D). Methods —We identified the novel DES mutation p.Glu401Asp in a large Spanish family with iLVAC/D and a high incidence of adverse cardiac events. A full clinical evaluation was performed on all mutation carriers and non-carriers to establish clinical and genetic co-segregation. In addition, desmin and intercalar disc-related proteins expression were histologically analyzed in explanted cardiac tissue affected by the DES mutation. Furthermore, mesenchymal stem cells were isolated and cultured from two family members with the DES mutation (one with mild and one with severe symptomatology) and a member without the mutation (control) and differentiated ex vivo to cardiomyocytes. Then, important genes related to cardiac differentiation and function were analyzed by qRT-PCR. Finally, the p.Glu401Asp mutated DES gene was transfected into cells lines and analyzed by confocal microscopy. Results —66 family members were screened for the DES -p.Glu401Asp mutation, 23 of them were positive, 6 were obligate carriers and 2 were likely carriers. 100 % of genotype positive patients presented data consistent with inherited arrhythmogenic cardiomyopathy/dysplasia (iAC/D) phenotype with variable disease severity expression, high incidence sudden cardiac death and absence of skeletal myopathy or conduction system disorders. Immunohistochemistry was compatible with iAC/D, and the functional study showed an abnormal growth pattern and cellular adhesion, reduced desmin RNA expression, as well as some other membrane proteins, and desmin aggregates in transfected cells expressing the mutant desmin. Conclusions —The DES -p.Glu401Asp mutation causes predominant iLVAC/D with a high incidence of adverse clinical events in the absence of skeletal myopathy or conduction system disorders. The pathogenic mechanism probably corresponds to an alteration in desmin dimer and oligomer assembly and its connection with membrane proteins within the intercalated disc.