**2.6 Other DCM genes**

*Cardiac Diseases - Novel Aspects of Cardiac Risk, Cardiorenal Pathology and Cardiac Interventions*

Mutations in the gene encoding dystrophin (*DMD*) cause severe muscle weakness and DCM in Duchenne muscular dystrophy (DMD). Because the *DMD* gene is located in the short arm of X chromosome, pathogenic mutations causing DMD mostly affect boys. The frequency of *DMD* caused muscular dystrophy and DCM is rare, with an estimated incidence 1 in 3500 male births worldwide [42]. Dystrophin protein is a key component of dystrophin-glycoprotein complex and plays a critical role in maintaining the structural integrity of sarcolemma during repeated cycles of muscle contraction and relaxation [43]. Mutations in *DMD* result in loss of the dystrophin protein expression that causes primary muscular dystrophy in males presenting with progressive muscle wasting at early childhood. Subsequently, cardiac dysfunction is involved and more than 90% of affected individuals manifest

Mutations in *DES* have been associated with a spectrum of cardiomyopathies, mostly notably DCM, in about 1–2% of cases [41]. Overlapping phenotypes of *DES* mutations including arrhythmia, cardiac conduction diseases, and skeletal myopa-

DCM and patient often died of cardiac and respiratory muscle failure [44].

that *BAG3* as a bona-fide disease susceptibility gene for DCM [48].

Mutations in the ion channel coding gene *SCN5A* are identified to cause DCM with strong supporting evidence. *SCN5A* encodes the sodium channel Nav1.5 that is mainly expressed in the cardiac muscle [49]. Mutations in *SCN5A* are associated primarily with conduction disorder, arrhythmia and DCM. Incidence of pathogenic *SCN5A* variants is estimated to be 2–4% in all DCM cases [50]. Missense mutations such as R222Q variant located in a voltage-sensing domain exert activating effects on sodium channel function and were thought to cause DCM. While guidelinebased heart failure therapies have moderate effect, drugs that have sodium channelblocking properties such as amiodarone or flecainide could substantially reduce DCM phenotype in patients with R222Q carriers [51]. Moreover, a recent report showed that quinidine treatment of a DCM patient with R222Q mutation achieved

The Z-disk is an anchoring plane for the actin (thin) filaments to attach and stabilize in the sarcomere. Mutations in many Z-disk-associated proteins coding genes result in cardiac disorders. *BAG3* encodes a highly conserved, Z-disk localized co-chaperone protein that is predominantly expressed in heart and skeletal muscle. BAG3 binds to the ATPase domain of the heat shock protein (Hsp) 70 and exerts multiple functions in regulating apoptosis, preserving the integrity of sarcomere, mediating unfolded protein response and autophagy. *BAG3* variants linked to DCM were firstly reported by two independent genome-wide association studies (GWASs). Later on*, BAG3* mutations were identified in 2–7% of DCM cases [45–47]. Genotype–phenotype correlation study revealed that DCM attributed by *BAG3* mutations is characterized by high penetrance in carriers more than 40 years of age. Patients with *BAG3* mutations are at a higher risk of developing a more severe and progressive heart failure compared with patients without *BAG3* mutations [46]. The level of BAG3 protein was reduced by about a half in both animal models of heart failure and DCM patients as well. Based on the evidence that truncation or deletion mutations in *BAG3* are associated with BAG3 haploinsufficiency which co-segregates with affected DCM family members, it was proposed that the decreased levels of BAG3 protein is the cause of DCM. BAG3 is also an independent heart failure risk factors associated with subclinical LV dysfunction. Thus, cumulative data support

thy and smooth muscle defects are frequently observed.

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**2.4 Z-disk gene**

**2.5 Ion channel gene**

*PLN* encodes phosphlamban, a transmembrane protein localized to the sarcoplasmic reticulum. Mutations in *PLN* cause variable DCM phenotype, with underlying mechanisms proposed through inhibiting the sarcoplasmic reticulum Ca2 + -ATPase (SERCA2a) [53]. While founder mutation R14del mutation in *PLN* is associated with severe phenotype with high risk for lethal ventricular arrhythmias and end-stage heart failure in the European [54], a milder phenotype had been reported from others [55], suggesting that genetic background might have a big impact on modifying the disease progression associated with *PLN* mutations caused DCM.

Mutations in genes other encoding the sarcoglycans (α, β, γ, δ) were also identified to cause DCM. The sarcoglycans are transmembrane proteins mainly expressed in heart and skeletal muscle that interact with dystrophin. α-, β-, γ-, and δ-sarcoglycans form the sarcoglycan complex that is key components of the dystrophin-associated glycoprotein complex, conferring structural integrity and stability to the sarcolemma through connecting the muscle fiber cytoskeleton to the extracellular matrix, and protecting muscle fibers from mechanical stress during muscle contraction. Mutations in sarcoglycans coding genes cause primary limbgirdle muscular dystrophy presented with early onset muscle weakness and associate with significant DCM [56]. Notably, mutations in the δ- sarcoglycan coding gene lead to DCM without involvement of obvious muscular dystrophy phenotypes [57].

Mutations in nuclear encoded mitochondrial genes such as *TAZ* and *DNAJC19* were also identified to cause DCM. *TAZ* encodes a mitochondrial localized Tafazzin protein that is predominantly expressed in cardiac and skeletal muscle. Tafazzin functions as a phospholipid transacylase that catalyzes the remodeling of cardiolipin that is required for oxidative phosphorylation. Mutations in the TAZ gene cause X-linked Barth syndrome and DCM, leading to premature death [58]. Mechanistically, mutations in *TAZ* result in Taffazin deficiency and cause mitochondrial dysfunction and impaired mitophagy and increased oxidative stress, leading to DCM [59].
