*2.4.2.2 Cytoskeleton protein location: force transmission and structural integrity*

The Z-disc is an electron-dense structure, in which titin and the thin filaments anchor. Critical components include α-actinin, which aligns actin and titin from neighboring sarcomeres and interacts with muscle LIM protein (MLP encoded by CSRP3). Telethonin (encoded by TCAP) is another Z-disc component interacting with titin and MLP to support overall sarcomere function. In addition, Cipher/Zband alternatively spliced PDZ-motif protein (Cipher/ZASP encoded by LDB3), which interacts with α-actinin-2 through a PDZ domain, an abundant protein interaction modules that recognize short amino acid motifs of the C-termini of target proteins, and couples to protein kinase C (PKC)-mediated signaling via its LIM domains [55, 56]. Gene mutations of multiple Z-disc proteins like MLP, cardiac ankyrin repeat protein (CARP), myopalladin, α-actinin 2, TCAP, and nexilin may result in DCM [52]. Cipher/ZASP mutations have been associated to isolated left ventricular dilatation or DCM with NCCM phenotype [50]. Metavinculin (encoded by VCL) attaches the thin filaments to the plasma membrane and plays a key role in force transmission. Gene mutations in metavinculin cause DCM by disruption of disc structure and actin-filament organization [55]. The costamere, a rib-like structure of the cytoplasmatic and transmembrane proteins, interconnects the cytoskeleton to the plasma membrane and the extracellular matrix. Dystrophin and its associated proteins, sacroglycans and dystroglycan, enrich at the costamere and protect against contraction-induced injury [52]. The integrity of the dystrophin complex is critical for mechano-transduction and loss of function mutations trigger instability of the plasma membrane and myofiber loss. This mechanism leads to Duchenne and Becker muscular dystrophy [57]. Desmin, another intermediate filament in cardiomyocytes, forms a 3D scaffold that extends across the entire diameter of the cardiomyocyte, surrounds the Z-discs and interlinks them together and integrates the contractile apparatus with the sarcolemma and the nucleus. Desmin helps to sense mechanical stretch and transduces downstream signals from extracellular to the nucleus. In addition, desmin plays a crucial role during myogenesis. Inhibition of desmin expression blocks myoblast fusion and myotube formation [58]. Mutations in the desmin genes are associated with an autosomal dominant skeletal myopathy, cardiac conduction block, and DCM [59]. Prevalence of desmin mutations in familial DCM have been reported in 1–2% [60].

**47**

*2.4.2.6 Ion channel*

*Current Pathophysiological and Genetic Aspects of Dilated Cardiomyopathy*

*2.4.2.3 Desmosomes: cell-cell adhesion and intracellular signaling/mechano-signaling*

Desmosomes are organized cell membrane structures that provide functional and structural contact between adjacent cells. Mutations in protein components of desmosomes like plakoglobin, desmoplakin, and plakophilin-2 can cause syndromic and nonsyndromic ARVC as well as DCM due to disruption of intercellular junction [55, 61].

Calcium enters the myocyte through voltage-gated L-type Ca2+-channels. This triggers the release of calcium from the sarcoplasmic reticulum (SR) via the ryanodine receptor 2 (RyR2). At low intracellular calcium concentrations, troponin I and actin interactions block actomyosin ATPase activity. With increasing intracellular concentration, calcium binds to troponin C, which releases troponin I inhibition and stimulates contraction. Calcium dissociates from troponin C in cardiac relaxation. Calcium concentration decreases by calcium reuptake in the SR through the phospholambanregulated cardiac sarcoplasmic reticulum CA2+-ATPase (SERCA2a) [55]. Mutations of phospholamban precipitate DCM by altering calcium homeostasis [54]. Specific phospholamban mutation R14del is associated with high risk of malignant ventricular arrhythmias and end-stage HF. Further, it is described in a phenotype of ARVC [62].

The nuclear membrane protein complex contains emerin and lamin A/C (LMNA) [52, 55]. These two lamina proteins and nesprin-1 are part of the LINC complex that links the nucleus to the cytoplasm. Stress signals in the cytoplasm are hypothesized to act with the LINC complex, affecting gene expression in the nucleus. The LINC complex is crucial for an appropriate transcriptional response of the cell to mechanical stress [52]. Defects in emerin proteins can induce X-linked Emery-Dreifuss muscular dystrophy, joint contractures, conduction system disease, and DCM. Dominant lamin A/C (encoded by LMNA) mutations exhibit a more cardiac-restricted phenotype with fibrofatty degeneration of the myocardium and it is conducting system. More than 200 different lamin A/C (LMNA) mutations are associated with inherited cardiomyopathy, primarily DCM that may be associated with conduction system disease prior to the evidence of ventricular dilatation due to fibrofatty degeneration of the myocardium and conducting cells [52, 55]. Other diseases caused by lamin A/C mutations are Charcot-Marie-Tooth neuropathy, Dunningan partial familial lipodystrophy, progeria and other overlapping syndromes, all known as laminopathies [63].

The function of sarcolemmal transmembrane cardiac voltage-gated sodium channel is crucial in the generation of cardiac action potentials. Some mutations in the encoding gene SCNA5 are implicated in DCM. SCN5A mutations causes high burden of arrhythmias. There are also many allelic variants in SCN5A, including those leading to Brugada syndrome, idiopathic ventricular fibrillation (VF), familial atrial fibrillation (AF), left ventricular non-compaction cardiomyopathy, and long QT syndrome type III [54, 59, 64].

Extracellular matrix proteins such as laminin alpha-4 (LAMA4) and Fukutin (FKTN) have been described in relation to DCM. They may lead to DCM phenotype

by disrupting signaling pathways and modifying cell-surface molecules [50].

The genetic evaluation of DCM is summarized in **Table 2**.

*DOI: http://dx.doi.org/10.5772/intechopen.83567*

*2.4.2.4 Sarcoplasmic reticulum: calcium homeostasis*

*2.4.2.5 Nuclear envelope: maintain structural organization*

*2.4.2.7 Extracellular matrix-cell-adhesion and signaling*

## *2.4.2.3 Desmosomes: cell-cell adhesion and intracellular signaling/mechano-signaling*

Desmosomes are organized cell membrane structures that provide functional and structural contact between adjacent cells. Mutations in protein components of desmosomes like plakoglobin, desmoplakin, and plakophilin-2 can cause syndromic and nonsyndromic ARVC as well as DCM due to disruption of intercellular junction [55, 61].
