Novel Desmin Mutation p.Glu401Asp Impairs Filament Formation, Disrupts Cell Membrane Integrity, and Causes Severe Arrhythmogenic Left Ventricular Cardiomyopathy/Dysplasia Bermúdez Jiménez, Francisco José Carriel Araya, Víctor Brodehl, Andreas Alaminos Mingorance, Miguel Campos Muñoz, Antonio Jesús Schirmer, Ilona Milting, Hendrik Álvarez Abril, Beatriz Álvarez, Miguel López Fernández, Silvia García-Giustiniani, Diego Monserrat, Lorenzo Tercedor, Luis Jiménez Jáimez, Juan Arrhythmogenic right ventricular dysplasia Desmin Mutation Myopathy, myofribillar, desmin-related Ventricular fibrillation Dr Milting was funded by grants from the German Research Foundation (MI 1146/2-1) and the Erich and Hanna Klessmann Foundation (Gütersloh, Germany). Histological, histochemical, immunohistochemical, real-time quantitative reverse transcription PCR, and mesenchymal stem cells differentiation studies were performed and supported by members of the Tissue Engineering Group of the Department of Histology of the University of Granada, Spain (Drs Carriel, Alaminos, and Campos). 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, 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. Methods:We identified the novel DES mutation p.Glu401Asp in a large Spanish family with inherited left ventricular arrhythmogenic cardiomyopathy/dysplasia and a high incidence of adverse cardiac events. A full clinical evaluation was performed on all mutation carriers and noncarriers to establish clinical and genetic cosegregation. 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 2 family members with the DES mutation (1 with mild and 1 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 real-time quantitative polymerase chain reaction. Finally, the p.Glu401Asp mutated DES gene was transfected into cell lines and analyzed by confocal microscopy. Results:Of the 66 family members screened for the DES-p.Glu401Asp mutation, 23 of them were positive, 6 were obligate carriers, and 2 were likely carriers. One hundred percent of genotype-positive patients presented data consistent with inherited arrhythmogenic cardiomyopathy/dysplasia phenotype with variable disease severity expression, high-incidence of sudden cardiac death, and absence of skeletal myopathy or conduction system disorders. Immunohistochemistry was compatible with inherited arrhythmogenic cardiomyopathy/dysplasia, and the functional study showed an abnormal growth pattern and cellular adhesion, reduced desmin RNA expression, and some other membrane proteins, as well, and desmin aggregates in transfected cells expressing the mutant desmin. Conclusions:The DES-p.Glu401Asp mutation causes predominant inherited left ventricular arrhythmogenic cardiomyopathy/dysplasia 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. 2024-02-23T13:10:40Z 2024-02-23T13:10:40Z 2018-04 journal article Bermúdez-Jiménez FJ, Carriel V, Brodehl A, Alaminos M, Campos A, Schirmer I, Milting H, Álvarez Abril B, Álvarez M, López-Fernández S, García-Giustiniani D, Monserrat L, Tercedor L, Jiménez-Jáimez J. The Novel Desmin Mutation p.Glu401Asp Impairs Filament Formation, Disrupts Cell Membrane Integrity and Causes Severe Arrhythmogenic Left Ventricular Cardiomyopathy/Dysplasia. Circulation. 2018 Apr 10;137(15):1595-1610. doi: 10.1161/CIRCULATIONAHA.117.028719 https://hdl.handle.net/10481/89514 10.1161/CIRCULATIONAHA.117.028719 eng http://creativecommons.org/licenses/by/4.0/ open access Atribución 4.0 Internacional American Heart Association