Cardiology Department, Virgen de las Nieves University Hospital, Granada, Spain (F.J.B.-J., B.A.A., M. Álvarez, S.L.-F., L.T., J.J.-J.).
Department of Histology, Tissue Engineering Group, Faculty of Medicine, University of Granada, Spain (F.J.B.-J., B.A.A., M. Álvarez, S.L.-F, L.T., J.J.-J., V.C., M. Alaminos, A.C.).
Circulation. 2018 Apr 10;137(15):1595-1610. doi: 10.1161/CIRCULATIONAHA.117.028719. Epub 2017 Dec 6.
Desmin () mutations cause severe skeletal and cardiac muscle disease with heterogeneous phenotypes. Recently, 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 -p.Glu401Asp mutation as a cause of inherited left ventricular arrhythmogenic cardiomyopathy/dysplasia.
We identified the novel 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 mutation. Furthermore, mesenchymal stem cells were isolated and cultured from 2 family members with the 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 gene was transfected into cell lines and analyzed by confocal microscopy.
Of the 66 family members screened for the -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 -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.
角蛋白 () 突变导致表现型异质性的严重骨骼肌和心肌疾病。最近，在遗传性心律失常性右心室心肌病/发育不良的患者中描述了 突变，尽管其细胞和分子发病机制尚不清楚。我们的目的是描述新型 -p.Glu401Asp 突变作为遗传性左心室心律失常性心肌病/发育不良的病因，并进行临床和功能分析。
我们在一个遗传性左心室心律失常性心肌病/发育不良且不良心脏事件发生率高的大型西班牙家族中发现了新型 -p.Glu401Asp 突变。对所有突变携带者和非携带者进行了全面的临床评估，以确定临床和遗传共分离。此外，还对突变影响的心脏组织进行了组织学分析，以确定角蛋白、闰盘相关蛋白的表达情况。此外，还从 2 名携带该突变的家族成员（1 名症状较轻，1 名症状较重）和 1 名无突变的家族成员（对照）中分离和培养了间充质干细胞，并在体外分化为心肌细胞。然后，通过实时定量聚合酶链反应分析与心脏分化和功能相关的重要基因。最后，将突变的 p.Glu401Asp 基因转染到细胞系中，并通过共聚焦显微镜进行分析。
在筛查 -p.Glu401Asp 突变的 66 名家族成员中，有 23 名阳性，6 名是必然携带者，2 名可能是携带者。100%的基因型阳性患者表现出与遗传性心律失常性心肌病/发育不良表型一致的数据，其疾病严重程度表现可变，发生心脏性猝死的概率较高，且无骨骼肌病或传导系统障碍。免疫组织化学符合遗传性心律失常性心肌病/发育不良，功能研究显示异常生长模式和细胞黏附，角蛋白 RNA 表达减少，以及其他一些膜蛋白，并且在表达突变角蛋白的转染细胞中出现角蛋白聚集。
-p.Glu401Asp 突变导致以遗传性左心室心律失常性心肌病/发育不良为主，且在无骨骼肌病或传导系统障碍的情况下，不良临床事件发生率较高。发病机制可能与角蛋白二聚体和多聚体组装的改变及其与闰盘中膜蛋白的连接有关。
