{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T04:19:14Z","timestamp":1791433154968,"version":"4.3.3"},"reference-count":54,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"15","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2018,4,10]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>\n                      Desmin (\n                      <jats:italic>DES<\/jats:italic>\n                      ) mutations cause severe skeletal and cardiac muscle disease with heterogeneous phenotypes. Recently,\n                      <jats:italic>DES<\/jats:italic>\n                      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\n                      <jats:italic>DES<\/jats:italic>\n                      -p.Glu401Asp mutation as a cause of inherited left ventricular arrhythmogenic cardiomyopathy\/dysplasia.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      We identified the novel\n                      <jats:italic>DES<\/jats:italic>\n                      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\u2013related proteins expression were histologically analyzed in explanted cardiac tissue affected by the\n                      <jats:italic>DES<\/jats:italic>\n                      mutation. Furthermore, mesenchymal stem cells were isolated and cultured from 2 family members with the\n                      <jats:italic>DES<\/jats:italic>\n                      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\n                      <jats:italic>DES<\/jats:italic>\n                      gene was transfected into cell lines and analyzed by confocal microscopy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      Of the 66 family members screened for the\n                      <jats:italic>DES<\/jats:italic>\n                      -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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>\n                      The\n                      <jats:italic>DES<\/jats:italic>\n                      -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.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.117.028719","type":"journal-article","created":{"date-parts":[[2017,12,6]],"date-time":"2017-12-06T05:15:20Z","timestamp":1512537320000},"page":"1595-1610","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":101,"title":["Novel Desmin Mutation p.Glu401Asp Impairs Filament Formation, Disrupts Cell Membrane Integrity, and Causes Severe Arrhythmogenic Left Ventricular Cardiomyopathy\/Dysplasia"],"prefix":"10.1161","volume":"137","author":[{"given":"Francisco Jos\u00e9","family":"Berm\u00fadez-Jim\u00e9nez","sequence":"first","affiliation":[{"name":"Cardiology Department, Virgen de las Nieves University Hospital, Granada, Spain (F.J.B.-J., B.A.A., M. \u00c1lvarez, S.L.-F., L.T., J.J.-J.)."},{"name":"Department of Histology, Tissue Engineering Group, Faculty of Medicine, University of Granada, Spain (F.J.B.-J., B.A.A., M. \u00c1lvarez, S.L.-F, L.T., J.J.-J., V.C., M. Alaminos, A.C.)."},{"name":"Instituto de Investigaci\u00f3n Biosanitaria (F.J.B.-J., B.A.A., M. \u00c1lvarez, S.L.-F, L.T., J.J.-J., V.C., M. Alaminos, A.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V\u00edctor","family":"Carriel","sequence":"additional","affiliation":[{"name":"Department of Histology, Tissue Engineering Group, Faculty of Medicine, University of Granada, Spain (F.J.B.-J., B.A.A., M. \u00c1lvarez, S.L.-F, L.T., J.J.-J., V.C., M. Alaminos, A.C.)."},{"name":"Instituto de Investigaci\u00f3n Biosanitaria (F.J.B.-J., B.A.A., M. \u00c1lvarez, S.L.-F, L.T., J.J.-J., V.C., M. Alaminos, A.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Brodehl","sequence":"additional","affiliation":[{"name":"Erich and Hanna Klessmann Institute for Cardiovascular Research and Development, Heart and Diabetes Centre North Rhine-Westphalia, Ruhr University Bochum, Bad Oeynhausen, Germany (A.B., I.S., H.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Alaminos","sequence":"additional","affiliation":[{"name":"Department of Histology, Tissue Engineering Group, Faculty of Medicine, University of Granada, Spain (F.J.B.-J., B.A.A., M. \u00c1lvarez, S.L.-F, L.T., J.J.-J., V.C., M. Alaminos, A.C.)."},{"name":"Instituto de Investigaci\u00f3n Biosanitaria (F.J.B.-J., B.A.A., M. \u00c1lvarez, S.L.-F, L.T., J.J.-J., V.C., M. Alaminos, A.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Campos","sequence":"additional","affiliation":[{"name":"Department of Histology, Tissue Engineering Group, Faculty of Medicine, University of Granada, Spain (F.J.B.-J., B.A.A., M. \u00c1lvarez, S.L.-F, L.T., J.J.-J., V.C., M. Alaminos, A.C.)."},{"name":"Instituto de Investigaci\u00f3n Biosanitaria (F.J.B.-J., B.A.A., M. \u00c1lvarez, S.L.-F, L.T., J.J.-J., V.C., M. 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