RT Journal Article
T1 Novel Desmin Mutation p.Glu401Asp Impairs Filament Formation, Disrupts Cell Membrane Integrity, and Causes Severe Arrhythmogenic Left Ventricular Cardiomyopathy/Dysplasia.
A1 Bermúdez-Jiménez, Francisco José
A1 Carriel, Víctor
A1 Brodehl, Andreas
A1 Alaminos, Miguel
A1 Campos, Antonio
A1 Schirmer, Ilona
A1 Milting, Hendrik
A1 Abril, Beatriz Álvarez
A1 Álvarez, Miguel
A1 López-Fernández, Silvia
A1 García-Giustiniani, Diego
A1 Monserrat, Lorenzo
A1 Tercedor, Luis
A1 Jiménez-Jáimez, Juan
K1 arrhythmogenic right ventricular dysplasia
K1 desmin
K1 mutation
K1 myopathy, myofibrillar, desmin-related
K1 ventricular fibrillation
AB 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. 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. 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. 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.
YR 2017
FD 2017-12-06
LK http://hdl.handle.net/10668/11883
UL http://hdl.handle.net/10668/11883
LA en
DS RISalud
RD Apr 9, 2025