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The author would like to express his appreciation to Ms. Sandra Keating and Mrs. Suzanne Tobias for editing the manuscript of this book chapter.

### **Author details**

Bandar Al‐Ghamdi

Address all correspondence to: balghamdi@kfshrc.edu.sa

Heart Centre, King Faisal Specialist Hospital and Research Centre, Alfaisal University, Riyadh, Saudi Arabia

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Saudi Arabia

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Address all correspondence to: balghamdi@kfshrc.edu.sa

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**Provisional chapter**

### **Complexity of Sarcomere Protein Gene Mutations in Restrictive Cardiomyopathy in Restrictive Cardiomyopathy**

**Complexity of Sarcomere Protein Gene Mutations** 

Shuai Wang and Daoquan Peng Shuai Wang and Daoquan Peng Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/66378

#### **Abstract**

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172 Cardiomyopathies - Types and Treatments

Restrictive cardiomyopathy (RCM) is characterized by impaired filling of the ventricles in the presence of normal wall thickness and systolic function. Although idiopathic RCM is rare compared to other types of cardiomyopathy, the effects are severe. Until recently, many sarcomere genes previously described to be causative mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy have been reported in RCM. Nowadays, it is accepted that primary RCM is also within the spectrum of sarcomere disease. However, the relationship between the identified mutations in sarcomere genes and clinical mani‐ festation are complex, and the possible pathogenic mechanisms are not fully understood. Besides, many RCM‐related sarcomere mutations were reported to cause variable clinical phenotype. Occasionally, "phenotype transition" may also be seen in an individual who was previously diagnosed with RCM.

**Keywords:** restrictive cardiomyopathy, sarcomere, gene mutation

### **1. Introduction**

Restrictive cardiomyopathy (RCM) is characterized by impaired filling of the ventricles in the presence of normal wall thickness and systolic function. While RCM is rare compared to other primary cardiomyopathies, most affected individuals have severe signs and symptoms of heart failure and majority die shortly after diagnosis unless they receive a cardiac transplant [1]. According to the etiology, RCM has been classified as primary or secondary. Secondary RCM refers to the conditions in association with local inflammation (Loeffler cardiomy‐ opathy, endomyocardial fibrosis, and eosinophilic endomyocardial disease) or infiltrative (amyloidosis and sarcoidosis) or storage disease (hemochromatosis, glycogen storage disease, and Fabry disease, etc.) [2]. Primary RCM includes RCM ascribed to inherited or sporadically acquired mutations or in many cases due to unknown etiology. So far, through mutation

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

screening of different individuals and families presenting the RCM phenotype, mutations in multiple sarcomere genes have been identified to be linked with RCM, which has greatly expanded our understanding about "idiopathic RCM." However, the relationship between the identified sarcomeric mutations and clinical manifestation are complex and many puzzles still exist. The mechanism behind the genotype‐phenotype correlation is not clearly under‐ stood. Most of these RCM‐associated sarcomeric mutations, when mutated at specific sites, are also known to induce HCM or DCM. Even people carrying the same mutation of the same sarcomeric gene may exhibit heterogenetic manifestations. "Phenotype transition" may even been seen at a late stage of RCM resulting in atypical RCM.

### **2. Multiple sarcomeric gene mutations in human RCM**

The sarcomere contains different protein involved in muscle contraction. Two major components are actin, which constitutes the backbone of the thin filament, and myosin, which makes up the thick filament. The interaction of myosin and actin causing the sliding of the thin filaments along the thick filaments results in muscle contraction and force development. Association and disas‐ sociation of myosin and actin are regulated in a Ca2+‐dependent manner by the troponin‐alphat‐ ropomysin (Tm) complex. The actin‐myosin contractile apparatus, which consists of five thin filament proteins (actin, tropomyosin, and troponin T, I, and C) and three thick filament proteins (myosin heavy chain, essential light chain, and regulatory light chain), plays a key role in regu‐ lating the sarcomere function. So far, except for troponin C, mutations in the other thin filament and thick filament proteins have all been identified in RCM. Besides, a series of mutations in other regulatory sarcomere proteins such as myosin‐binding protein C, titin, and Z‐disc proteins also have been recognized to induce diastolic dysfunction resulting in a restrictive phenotype.

### **2.1. Cardiac troponin mutation**

Cardiac troponin is located at regular intervals along the thin filament and consists of three sub‐ units: cardiac troponin C (cTnC), troponin I (cTnI), and troponin T (cTnT). cTnC acts as a Ca2+ sensor, which confers Ca2+ sensitivity to muscle contraction [3]. Cardiac TnI is the inhibitory subunit, primarily functioning to prevent actin and myosin from interacting in the absence of Ca2+. The cTnT subunit binds to tropomyosin (Tm) and is responsible for transmitting the Ca2+‐ binding signal from cTn to Tm [4]. Electrical depolarization of the cell membrane opens the L‐type calcium channels and allows Ca2+ influx, which incites release of Ca2+ from sarcoplasmic reticulum due to opening of the ryanodine receptors. The released Ca2+ binds to cardiac tropo‐ nin C and induces conformational changes in the troponin T‐tropomyosin complex, resulting in displacement of cTnI from actin and subsequent association of actin with myosin. Currently, nine mutations in genes encoding cTnI and three dominant mutations in genes encoding cTnT have been reported in human RCM and no mutations have been identified in cTnC yet.

#### *2.1.1. Troponin I mutation*

The gene of cardiac TnI (*TNNI3*) is situated on the 19th chromosome (19q13.4) and consists of eight exons and seven introns. The mature molecule of cTnI is 209 a.a long and consists of five domains: (1) N‐terminal domains, (2) IT‐arm, (3) inhibitory domain, (4) regulatory domain, and (5) C‐terminal mobile domains [5]. Until now, RCM‐related cTnI mutations are found located in the inhibitory domain and the C‐terminal domain.

### *2.1.1.1. Missense mutations located at the inhibitory domain*

screening of different individuals and families presenting the RCM phenotype, mutations in multiple sarcomere genes have been identified to be linked with RCM, which has greatly expanded our understanding about "idiopathic RCM." However, the relationship between the identified sarcomeric mutations and clinical manifestation are complex and many puzzles still exist. The mechanism behind the genotype‐phenotype correlation is not clearly under‐ stood. Most of these RCM‐associated sarcomeric mutations, when mutated at specific sites, are also known to induce HCM or DCM. Even people carrying the same mutation of the same sarcomeric gene may exhibit heterogenetic manifestations. "Phenotype transition" may even

The sarcomere contains different protein involved in muscle contraction. Two major components are actin, which constitutes the backbone of the thin filament, and myosin, which makes up the thick filament. The interaction of myosin and actin causing the sliding of the thin filaments along the thick filaments results in muscle contraction and force development. Association and disas‐ sociation of myosin and actin are regulated in a Ca2+‐dependent manner by the troponin‐alphat‐ ropomysin (Tm) complex. The actin‐myosin contractile apparatus, which consists of five thin filament proteins (actin, tropomyosin, and troponin T, I, and C) and three thick filament proteins (myosin heavy chain, essential light chain, and regulatory light chain), plays a key role in regu‐ lating the sarcomere function. So far, except for troponin C, mutations in the other thin filament and thick filament proteins have all been identified in RCM. Besides, a series of mutations in other regulatory sarcomere proteins such as myosin‐binding protein C, titin, and Z‐disc proteins also have been recognized to induce diastolic dysfunction resulting in a restrictive phenotype.

Cardiac troponin is located at regular intervals along the thin filament and consists of three sub‐ units: cardiac troponin C (cTnC), troponin I (cTnI), and troponin T (cTnT). cTnC acts as a Ca2+ sensor, which confers Ca2+ sensitivity to muscle contraction [3]. Cardiac TnI is the inhibitory subunit, primarily functioning to prevent actin and myosin from interacting in the absence of Ca2+. The cTnT subunit binds to tropomyosin (Tm) and is responsible for transmitting the Ca2+‐ binding signal from cTn to Tm [4]. Electrical depolarization of the cell membrane opens the L‐type calcium channels and allows Ca2+ influx, which incites release of Ca2+ from sarcoplasmic reticulum due to opening of the ryanodine receptors. The released Ca2+ binds to cardiac tropo‐ nin C and induces conformational changes in the troponin T‐tropomyosin complex, resulting in displacement of cTnI from actin and subsequent association of actin with myosin. Currently, nine mutations in genes encoding cTnI and three dominant mutations in genes encoding cTnT have been reported in human RCM and no mutations have been identified in cTnC yet.

The gene of cardiac TnI (*TNNI3*) is situated on the 19th chromosome (19q13.4) and consists of eight exons and seven introns. The mature molecule of cTnI is 209 a.a long and consists of five

been seen at a late stage of RCM resulting in atypical RCM.

**2.1. Cardiac troponin mutation**

174 Cardiomyopathies - Types and Treatments

*2.1.1. Troponin I mutation*

**2. Multiple sarcomeric gene mutations in human RCM**

The inhibitory domain of hcTnI spans residues 137–148 [6, 7], some also reported a differ‐ ent border of this region (residues 129–148) [6, 8]. In the absence of Ca2+, residues 138–148 of the inhibitory domain interact with actin [9] and shift the tropomyosin molecule, impeding the antomyosin‐complex formation [10]. Two of the RCM mutations are localized within this important region. The first one is 797T→A nucleotide substitution of exon 7, which led to a Leu144Gln (L144Q) amino acid substitution [11]. The second mutation is 799C→T nucleotide substitution of exon 7 that leads to an Arg145Trp (R145W) amino acid substitution [11].

Data from *in vitro* experiment showed that both L144Q and R145W alter myofilament sen‐ sitivity to Ca2+. Skinned cardiac fiber experiment, which measures the Ca2+‐buffering capac‐ ity of the myofilament while measuring the development of tension and maximal force, revealed that these two mutations resulted in increase of Ca2+ sensitivity of force development in skinned fibers from transgenic mice. In addition, a significant increase in the basal force was shown compared to WT cardiac fiber [12]. Measurement of myofilament ATPase activ‐ ity revealed that L144Q and R145W mutant showed an increase in the basal ATPase at low Ca2+ concentrations. Besides, fibers from these two mutants exhibited markedly increased Ca2+ sensitivity of ATPase activity [13].

#### *2.1.1.2. Missense mutations located at the mobile C-terminal domain*

The mobile C‐terminal domain of hcTnI is further divided into the H4 α‐helix (residues 164– 188) and the C‐terminal part (residues 199–210) [5]. 865G→A nucleotide substitution of exon 7 that led to an Ala171Thr amino acid substitution and an 886A→G nucleotide substitution of exon 7, which resulted in a Lys178Glu (K178E) amino acid substitution both occurred within the H4 α‐helix region and have been identified in RCM patients. Since these two mutations are known to be located within the actin‐binding sites (residues 173–181) [14, 15], K178E and Ala171Thr mutations may influence the inhibitory function through actin binding.

Although the structure of the C‐terminal part of hcTnI which consists of residues 190–210 is not fully understood, it is critical for a full inhibitory activity and Ca2+ sensitivity of force development because it binds to actin and helps to maintain the thin filament in a blocked state [16]. Mutations occurred at the C‐terminal domain may destabilize or decrease its inter‐ actions with actin in the absence of Ca2+, consequently relieving cTnI inhibition [17]. Up to now, RCM‐related mutant Asp190His (D190H), Arg192His (R192H), and Arg204His (R204H) have been localized within the conserved C‐terminal region of the protein [11, 18]. *In vitro* experiments revealed that two of these mutants D190H and R192H markedly increased the filament sensitivity to Ca2+, while another mutation R204H has been reported to result in a dis‐ ruption of the normal interaction between cTnI‐cTnC and cTnI‐cTnT. It remains to be further determined what conformational changes happened in these mutant that lead to disrupted interaction between cTnI‐actin and cTnI‐cTnC.

### *2.1.1.3. Two deletion mutations*

Deletion of nucleotides usually causes frame shift and the introduction of a premature stop codon. Two deletion mutations of *TNNI3* which impaired relaxation of myocardium and resulted in a restrictive filling pattern were reported to be located in exon 7 and cause trun‐ cation of C‐terminal portion of cTnI. The truncated cTnI which lost its C‐terminal portion is susceptible to degradation and has reduced inhibitory capacity on the thin filament since C‐terminal contains the second binding domain for actin and cTnC [19, 20].

### *2.1.2. Troponin T mutation*

cTnT anchors the troponin complex to Tm and plays a critical role in modulating ATPase activation when Ca2+ concentrations achieve threshold levels. Until now, three different muta‐ tions in the cTnT gene (*TNNT2*) linked to RCM have been identified. However, the molecular pathogenesis of these cTnT mutations is not clear [20–22].
