Cardiomyopathy is a major cause of death worldwide. Based on pathohistological abnormalities and clinical manifestation, cardiomyopathies are categorized into several groups: hypertrophic, dilated, restricted, arrhythmogenic right ventricular, and unclassified. Dilated cardiomyopathy, which is characterized by dilation of the left ventricle and systolic dysfunction, is the most severe and prevalent form of cardiomyopathy and usually requires heart transplantation. Its etiology remains unclear. Recent genetic studies of single gene mutations have provided significant insights into the complex processes of cardiac dysfunction. To date, over 40 genes have been demonstrated to contribute to dilated cardiomyopathy. With advances in genetic screening techniques, novel genes associated with this disease are continuously being identified. The respective gene products can be classified into several functional groups such as sarcomere proteins, structural proteins, ion channels, and nuclear envelope proteins. Nuclear envelope proteins are emerging as potential molecular targets in dilated cardiomyopathy. Because they are not directly associated with contractile force generation and transmission, the molecular pathways through which these proteins cause cardiac muscle disorder remain unclear. However, nuclear envelope proteins are involved in many essential cellular processes. Therefore, integrating apparently distinct cellular processes is of great interest in elucidating the etiology of dilated cardiomyopathy. In this mini review, we summarize the genetic factors associated with dilated cardiomyopathy and discuss their cellular functions.
Cardiomyopathy is a main cause of death in most developed countries (Mortality and Causes of Death, 2015). According to the American Heart Association’s definition, cardiomyopathy is a group of diseases of the myocardium characterized by improper ventricular hypertrophy or dilation, and lead to mechanical and electrical dysfunction of the heart (Maron et al., 2006). Based on morphological abnormalities and clinical manifestations, cardiomyopathies are classified as hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), restrictive cardiomyopathy (RCM), LV noncompaction, conduction system disease, ion channelopathies, myocarditis (inflammatory cardiomyopathy), or stress cardiomyopathy.
Patients with DCM typically exhibit enlargement of the left ventricular chamber and often experience systolic abnormalities. DCM is the third leading cause of heart failure and frequently requires heart transplantation (Maron et al., 2006). The estimated prevalence of DCM is 1:2,500?3,000 (Codd et al., 1989; Miura et al., 2002). Moreover, approximately 20?35% of DCMs is familial and is associated with at least 40 genes or loci. With advances in genetic technologies used for diagnosis of DCMs, the number of genes proposed to contribute to cardiomyopathy has increased to at least 100 (Dellefave and McNally, 2010). Genetic alterations detected in patients with familial DCM are usually inherited in a dominant-negative manner. Although only a subset of DCM is caused by specific gene mutations, studies of these gene mutations and their phenotypes will provide molecular insights into the etiology of DCM.
Familial DCM was once considered a single specific disease; however, it is now known to have heterogeneous histopathological features and penetrance according to the causative gene mutations. Genes associated with DCMs are classified into several groups, including genes encoding nuclear envelope proteins, sarcomere proteins, structural proteins, ion channels, and unclassified proteins (Dellefave and McNally, 2010). In this review, we will discuss known genetic causes and cellular processes underlying DCM.
Myofibril consists of a basic unit called the sarcomere (Fig. 1). Contractile force generation in cardiomyocytes and its faithful delivery to the extracellular matrix and neighboring cells are essential for heart function. Over 300 mutations in sarcomere proteins have been shown as causes of DCM and other heart diseases (Morita et al., 2005). Human genetic studies have shown that many familial DCM cases are linked to alterations in sarcomere proteins such as cardiac actin (
Among genes encoding these proteins, mutations in
Various titin isoforms form a separate filamentous system in the sarcomere; this system provides elasticity and structural integrity to the sarcomere. Titin isoforms range from 3.0 to 3.8 mega Daltons in molecular weight and are encoded by the single gene
Normal heart function requires faithful delivery of contractile force from the sarcomere to the plasma membrane (the sarcolemma for muscle cells) and the extracellular matrix. Multiple filamentous systems that physically connect the sarcomere to the sarcolemma are thought to play critical roles in force transmission (Fig. 1). Desmin, encoded by the
The connections among sarcomeric actin, dystrophin, dystrophin-associated proteins, and the extracellular matrix also play important roles in force transmission and provide structural integrity to the sarcolemma. Dystrophin is a 427-kDa rod-shape cytoplasmic protein. An actin-binding domain in the N-terminus and dystroglycan complex-binding domain in the C-terminus are divided by a long central rod domain. Although mutations in dystrophin manifest as skeletal muscular dystrophy, affected individuals also exhibit DCM phenotypes.
Abnormal calcium homeostasis can also cause DCM and other heart diseases. Ca2+ enters cardiomyocytes through voltage-gated calcium channels (LTCCs) embedded in the sarcolemma. Influx of Ca2+ triggers opening of the RyR calcium channel in the sarcoplasmic reticulum (SR), which initiates sarcomere contraction. Re-influx of released cytoplasmic Ca2+ into the SR to relax the sarcomere is mediated by the SR calcium-ATPase pump (SERCA2a). Phospholamban, encoded by the
Dysfunction of cardiac ion channel proteins appears to cause DCM. The
The nuclear envelope consists of inner and outer nuclear membranes, being divided by a perinuclear space (Fig. 1) (Stewart et al., 2007). The nuclear lamina is a protein meshwork located beneath the inner nuclear membrane (Butin-Israeli et al., 2012). Lamin proteins are the major components of the nuclear lamina. In mammals, three lamin genes, i.e.
Mutations causing AD-EDMD identified by an initial genetic analysis include Q6X, R453W, R527P, and L530P; these mutations are enriched in the C-terminal tail domain of lamin A/C (Bonne et al., 1999). Later studies showed that AD-EDMD also results from H222Y and R249Q mutations (Bonne et al., 2000; Raffaele Di Barletta et al., 2000). A family study revealed that
The mice then die at approximately 16?18 days of age, exhibiting defective postnatal development in multiple tissues; therefore, this is the mouse model closest to complete
Mouse models of
DCM is a life-threatening disease that frequently results in heart failure. Identifying genetic factors that cause the clinical manifestation of a disease is required for defining the molecular trigger that initiates the disorder and the cellular response to the trigger. Moreover, complete profiling of the genetic causes of a disease is beneficial for an accurate diagnosis, particularly for diseases in which the clinical outcome is unclear or overlaps with other diseases. To date, genetic analyses of patients with familial DCM have shown causative relationships for mutations in more than 40 genes. These gene products are classified as sarcomere and structural proteins, ion channels, and nuclear envelope components. Profound insights into the molecular etiology of DCM have been provided by these discoveries. Failure of contractile force generation and transfer to the extracellular matrix, inefficient Ca2+ cycling, defective ion transport, and nuclear fragility can lead to dilation of ventricles and systolic dysfunction. Although current treatment of DCM is largely limited to the alleviation of clinical symptoms, further elucidation of these molecular processes and their cellular responses should provide new strategies to cure or mitigate cardiac dysfunction and heart failure. Moreover, monogenic genetic disorders such as familial DCM may be excellent targets for gene editing technology. The CRISPR/Cas9 system binds to the target sequence in the genome and generates double-stranded breaks with an unprecedented high efficiency. Mutated genes can be replaced by correct sequences via homology-directed repair (HDR). Indeed, the CRISPR/Cas9 system has been used to successfully correct dystrophin gene mutations in mdx mice. Therefore, this newly emerged technique is of great interest for therapies to treat human patients with familial DCM.