Autosomal dominant transmission of hypertrophic cardiomyopathy (Fig. 213-4) implies that (a) affected individuals are heterozygous for a disease-causing mutation; (b) affected members of one family share the same mutation; (c) 50 percent of the offspring of affected individuals will inherit the disorder; and (d) males and females are equally likely to inherit the disease gene. Despite these facts, clinical studies of hypertrophic cardiomyopathy indicate considerable variation in disease penetrance and expressivity. Heterogeneity of genetic etiology is an important factor for interfamilial differences of hypertrophic cardiomyopathy. Identification of the genetic and environmental influences that affect disease expression in affected members within the same family remains an important research endeavor.5
Over the past decade, a large number of gene mutations that cause hypertrophic cardiomyopathy have been identified using positional cloning methods. Early investigations focused on genetic linkage (mapping) strategies to define disease loci.80–83 Genetic mapping involves identifying DNA segments, usually identified by a sequence polymorphism that is coinherited with disease. The likelihood that a particular pattern of coinheritance would have been observed by random chance, termed LOD (logarithm of the odds), is calculated to determine the statistical significance of the observed segregation pattern. LOD scores ≥3 (indicating odds ≥1:1000) are considered significant. Linkage analyses of several unrelated large pedigrees with hypertrophic cardiomyopathy resulted in LOD scores ≥10 (odds ≥1:10,000,000) and defined 4 distinct disease loci in the human genome. These studies provided the first evidence of genetic heterogeneity in hypertrophic cardiomyopathy and indicated that mutations in different genes could cause clinically identical disease.
Subsequent genetic linkage studies enable investigators to narrow the disease intervals for hypertrophic cardiomyopathy below 5 cM (1 cM approximates 1 million base pairs of DNA). Candidate disease genes were readily identified at four familial hypertrophic cardiomyopathy (FHC) loci: β-cardiac myosin heavy chain; cardiac troponin T; α-tropomyosin; and cardiac myosin binding protein C. The nucleotide sequences of each gene were screened and sequence variants were found in samples from affected individuals that were absent in unaffected family members and normal control samples. Sequence variants were identified in codons that are highly conserved throughout evolution and predicted to encode proteins with significantly altered structure and presumably function, thereby fulfilling standard criteria as disease-causing mutations. These genome-wide mapping strategies defined four disease genes that encode sarcomere components: β-cardiac myosin heavy chain; cardiac troponin T; α-tropomyosin; and cardiac myosin-binding protein C (Table 213-1). Four other disease genes—cardiac actin, cardiac troponin I, regulatory myosin light chain, and essential myosin light chain—were identified by hypothesizing that mutations in other sarcomere protein genes would also cause hypertrophic cardiomyopathy. The sarcomere is the functional unit of contraction in muscle cells.
Table 213-1: Genes that are Mutated in Hypertrophic Cardiomyopathy |Favorite Table|Download (.pdf) Table 213-1: Genes that are Mutated in Hypertrophic Cardiomyopathy
|Disease gene ||Chromosome ||Band ||Locus ||Location (cM)* ||%† ||Method § |
|Cardiac troponin T ||1 ||q32 || TNNT2 ||219.85 ||~15 ||L |
|Essential myosin light chain ||3 ||p21.2-21.3 || MYL3 ||58.748 ||<1 ||C |
|? ||7 ||q34 ||? ||160.300 ||? ||L |
|Cardiac myosinbinding protein C ||11 ||p11.2 || MYBPC3 ||57.492 ||>15 ||L |
|Regulatory myosin light chain ||12 ||q23-24 || MYL2 ||113.441 ||<1 ||C |
| β-Cardiac myosin heavy chain ||14 ||q11.2-13 || MYH7 ||30.027 ||>35 ||L |
|Cardiac actin ||15 ||q14 || ACTC ||49.600 ||<5 ||L |
|α-Tropomyosin ||15 ||q22 || TPM1 ||69.940 ||<5 ||L |
|Cardiac troponin I ||19 ||q13.4 || TNN13 ||62.936 ||~10 ||C |
Sarcomere proteins are organized into interdigitating thick and thin filaments (Fig. 213-6) that cyclically attach and detach during contraction and relaxation, fueled by hydrolysis of ATP.84 Most hypertrophic cardiomyopathy mutations are predicted to encode stable proteins;85 hence, these mutations are unlikely to alter the stoichiometry of sarcomere components. Rather, these defects appear to cause disease through dominant negative mechanisms: mutant peptides are incorporated into the sarcomere and perturb function. Cardiac hypertrophy and ventricular remodeling can be viewed as compensatory responses to the biophysical consequences of a mutation and as such may provide an index to sarcomere dysfunction. A wide range of clinical responses to hypertrophic mutations is therefore not unexpected; responses might be expected to vary depending on whether the mutant peptide interferes with calcium cycling, crossbridge formation, or another sarcomere function. A comprehensive understanding of hypertrophic cardiomyopathy mutations will, therefore, ultimately require integration of molecular, biophysical, and clinical data. Although this information is far from complete, more detailed insights are on the horizon, from the increasing acquisition of clinical data, in vitro structure-function analyses of sarcomere proteins, and genetic engineering of human hypertrophic cardiomyopathy mutations into murine models of disease.
Mutations in cardiac sarcomere proteins cause hypertrophic cardiomyopathy. Mutations in genes that encode components of the thick filament (β-cardiac myosin heavy chain, myosin essential and regulatory light chains, myosin-binding protein C) and thin filament (troponin T, troponin I, α-tropomyosin, and actin) have been identified.
Mutations of Thin Filament Protein
Mutations in genes encoding several components of sarcomere thin filaments cause hypertrophic cardiomyopathy. Thin filament proteins including actin, tropomyosin, and the troponin complex (troponins C, I, and T) interact with the thick filament and anchor the sarcomere to the cytoskeleton (Fig. 213-6). Actin subunits polymerize to form double-helical strands: one end of actin filaments forms crossbridges with myosin, while the other end binds the sarcomere (at Z-bands) to intercalated disks via interactions with actinin (Fig. 213-7 B), and to the extracellular matrix via dystrophin.86 The helical filaments formed from tropomyosin intertwine with actin.87 Each tropomyosin dimer spans seven actin monomers and interacts with one troponin complex. The troponin-tropomyosin complex provides a calcium-sensitive switch that regulates actomyosin crossbridge formation.88 Troponin I is an inhibitory component; in the absence of calcium, troponin I binds actin and inhibits actomyosin ATPase activity. Calcium binding of troponin C releases actin from the troponin-tropomyosin complex and allows actin-myosin interactions. With the exception of troponin T, hypertrophic cardiomyopathy mutations have been found in each of these thin filament components.
Schematic of the cardiac actin gene and mutations that cause cardiac pathologies. A, Missense mutation Ala295Ser causes hypertrophic cardiomyopathy while Arg312His and Glu361Gly cause dilated cardiomyopathy. B, Schematic of potential interactions altered by distinct actin mutations. The hypertrophic defect may perturb force production by the sarcomere, whereas defects that cause dilated cardiomyopathy may impair force transmission to the cytoskeleton and extracellular matrix.90
Of the 20 actin genes in the human genome, 4 are expressed in cardiac, skeletal, or smooth muscle.86 Human α-cardiac actin is a 375-amino-acid polypeptide protein (41 kDa) encoded in 6 exons of the cardiac actin gene (designated ACTC; Fig. 213-7 A). α-Cardiac actin is expressed extensively throughout the myocardium and less abundantly in a variety of tissues.89 Actin mutations are a rare cause of hypertrophic cardiomyopathy, and to date, only one mutation, Ala295Ser, has been identified.90 The Ala295Ser mutation appears to be near a putative myosin-binding site and produces a relatively mild form of FHC. Intriguingly, mutations in the cardiac actin gene can also cause familial dilated cardiomyopathy, a pathology characterized by chamber dilation and reduced contractile function.91 Actin mutations that produce dilated cardiomyopathy are missense defects (Glu361Gly and Arg312Ala); these are predicted to disrupt interactions between actin filaments and the extracellular matrix (Fig. 213-7 B). After comparing the clinical consequences of different actin missense mutations, Mogensen et al.90 suggested that defects, which impair force generation and interaction with the thick filament, cause hypertrophic cardiomyopathy; mutations that impair interaction with the extracellular matrix resulted in dilated cardiomyopathy. To date, this provides the only example of distinct sarcomere mutations resulting in different clinical (dilated versus hypertrophic) phenotypes.
There are four tropomyosin genes in the human genome.87 The α-tropomyosin gene (designated TPM1) on chromosome 1592 is organized into 15 exons (Fig. 213-8); alternative splicing results in transcripts encoding a 284-amino-acid polypeptide (34 kDa) found in both fast skeletal and cardiac muscle.89 Mutations in α-tropomyosin cause only a small fraction (<5 percent) of hypertrophic cardiomyopathy92 and account for both familial94–96 and sporadic disease.40 Studies of Finnish populations indicate a founder effect of α-tropomyosin mutation Asp175Asn; 25 percent of affected individuals shared the defect.97 The Asp175Asn arises by a G → A transition of nucleotide residue 579, a mutation that has been observed to independently occur in affected families around the world,98 thereby implying increased susceptibility of this residue to mutation. Notably, the severity and distribution of ventricular hypertrophy in individuals with this defect varied considerably, thus indicating that the hypertrophic response is modulated by factors other than disease-causing mutation.5 Survival of individuals with α-tropomyosin mutations appears to be relatively good;96,98 life expectancy is longer than that observed in individuals with mutations in cardiac troponin T or with severe β-cardiac myosin heavy chain gene mutations (Fig. 213-9).
Schematic of the α-tropomyosin gene and mutations that cause hypertrophic cardiomyopathy. Mutation of nucleotide residue 579 (Asp175Asn) has independently occurred multiple times.98
Genetic etiology of hypertrophic cardiomyopathy influences survival. Kaplan-Meier curves demonstrate that life expectancy is similar in hypertrophic cardiomyopathy caused by α-tropomyosin mutation Asp175Asn, β-cardiac myosin heavy chain Val606Met, or myosin-binding protein C mutation InsG791, and significantly better (p<0.001) than that observed with mutations troponin T Arg92Gln or β-cardiac myosin heavy chain Arg403Gln. (Based on data in references41,93, and 98 .)
An intriguing aspect of α-tropomyosin defects is their lack of clinical expression outside of the heart despite an abundance of α-tropomyosin in skeletal muscle. This may be related to the location of hypertrophic cardiomyopathy mutations, all of which occur in exons that encode interactions with the cardiac-specific isoform troponin T. However, analyses of contractile parameters of skeletal muscle fibers from the vastus lateralis in individuals with the Asp175Asn mutation demonstrated differences in calcium sensitivity compared to normal muscle, although maximal force and shortening velocities were equivalent.99 Sensitivity to calcium may be, therefore, a critical determinant in the response of cardiac versus skeletal muscle to α-tropomyosin mutation.
The cardiac troponin T gene (TNNT2) spans 17 kb of DNA on chromosome 1 and is one of three troponin T genes in the human genome.100 A 288-amino-acid polypeptide (36 to 39 kDa) is encoded in 16 exons (Fig. 213-10) and several splice isoforms have been found in cardiac tissue. Approximately 15 percent of hypertrophic cardiomyopathy is caused by cardiac troponin T defects93 and multiple disease-causing mutations have been reported.93,94,101–103 While many are missense, splice signal mutations, insertions, and deletions have also been identified. Some defects may result in truncated polypeptides, but investigations using in vitro experimental systems suggest that both foreshortened and missense mutant peptides are stable and perturb contractile function. Truncated mutant troponin T peptides expressed in quail myotubes were incorporated into sarcomeres and cause markedly reduced calcium-activated force generation,104 indicating that hypertrophic cardiomyopathy mutations cause disease through a dominant negative effect on the sarcomere.
Schematic of the cardiac troponin T gene and mutations that cause hypertrophic cardiomyopathy. Exons that encode domains that interact with α-tropomyosin (α TM), cardiac troponin C and I (TnC and TnI, respectively) are indicated. In addition to missense mutations, defects have been identified that are predicted to truncate the peptide (deletions [Δ] and mutations in splice signals [G1 → A]).
The clinical phenotype resulting from cardiac troponin T mutations is characterized by only mild to modest hypertrophy and some genetically affected adults fail to fulfill standard criteria for diagnosis. The mean maximal left ventricular wall thickness resulting from 6 different cardiac troponin T mutations was 16.7 ± 5.5 mm,93 whereas the mean maximal left ventricular wall thickness observed with β-cardiac myosin heavy chain mutations was 23.7 ± 7.7 mm. Despite the minimal hypertrophic response produced by these mutations, shortened life expectancy and high incidences of sudden death characterize most cardiac troponin T defects93,102 (Fig. 213-9), although “benign” mutations have been reported.105 Troponin T mutations therefore cause significant diagnostic and management challenges for clinicians. At present neither molecular signals nor biophysical events have been defined that explain why these mutations produce only a modest hypertrophic response but marked electrical instability. Characterization of recently developed transgenic mice expressing mutant troponin T peptides provides important reagents for addressing these questions.
There are three troponin I genes in the human genome, but only the cardiac isoform (designated TNTI3) encoded on chromosome 19q13 is expressed at high levels in the myocardium. Eight exons in the cardiac troponin I gene (Fig. 213-11) encode a 210-amino-acid (27 to 31 kDa) polypeptide.106 Direct analyses of troponin I gene sequences in hypertrophic populations indicate that less than 5 percent of disease is caused by these mutations. In most patients, disease manifestations are similar to those produced by mutations in other sarcomere protein genes, although some patients exhibit apical hypertrophy or preexcitation syndrome (Wolf-Parkinson-White syndrome).107,108 Survival in hypertrophic cardiomyopathy due to cardiac troponin I mutations has not been assessed.
Schematic of the cardiac troponin I gene and mutations that cause hypertrophic cardiomyopathy. Most defects are missense, predicting a dominant negative mechanism for disease.
Mutations of Thick Filament Proteins
Mutations in genes encoding components of the sarcomere thick filament are the most common cause of hypertrophic cardiomyopathy and defects have been identified in β-cardiac myosin heavy chain, regulatory myosin light chain, essential myosin light chain, and cardiac myosin binding protein C (Table 213-1). Thick filament proteins participate and modulate force generation and anchor the sarcomere to the cytoskeleton84 (Fig. 213-6). β-Cardiac myosin heavy chains are central to force production through actin-myosin interactions and ATPase activity.109 Sequential formation and detachment of crossbridges between the myosin head and actin results in stepwise displacement of the actin filament relative to the myosin filament.110 Hydrolysis of ATP bound to the myosin head provides energy for detachment. Myosin light chains are calcium-binding proteins that optimize both the speed and efficiency of crossbridge cycling.111–113 Myosin-binding protein C modulates contraction by positioning the myosin head relative to the thin filament114–116 in response to phosphorylation. This molecule is arrayed in transverse stripes of the A-bands where it tethers the sarcomere to the cytoskeleton through interactions with myosin and titin.117
β-Cardiac Myosin Heavy Chain
Cardiac myosin heavy chains comprise approximately 1 percent of total myocyte protein. These large polypeptides contain 1935 amino acid residues (>200,000 kDa) that are folded into two domains (Fig. 213-12)—an N-terminal globular head region and a carboxyl rod region.109,110 Of more than 20 myosin heavy chain genes in the genome, only two are expressed in the heart,84 α-cardiac myosin heavy chain (MYH6) and β-cardiac myosin heavy chain (MYH7); both are encoded on chromosome 14 and separated by only 3700 bp.118 The amino acid sequences of amino α- and β-isoforms are 92.8 percent identical, but ATPase activity and the velocity of shortening associated with these two cardiac myosin heavy chains differ considerably.119,120 In the neonatal human cardiac ventricle, more than 60 percent of myosin heavy chains are the α-isoform. However, shortly after birth expression switches and during adult life the β-isoform predominates (greater than 90 percent) in the ventricles. By contrast, the α-cardiac myosin heavy chain remains the predominant isoform in adult human atria.118
Missense mutations in the β-cardiac myosin heavy chain cause hypertrophic cardiomyopathy. A schematic of the gene and encoded head and rod domains (open box) of the peptide are shown. Most defects alter sequences in the head or head-rod junction. Conservative mutations (0) may have less impact on survival than do substitutions that alter the charge of the residue (+1, +2, −1).
Approximately 35 percent of individuals with familial hypertrophic cardiomyopathy have a β-cardiac myosin heavy chain mutation and more than 40 distinct defects have been identified.26,27,38,39,53,123–130 De novo β-cardiac myosin heavy chain mutations have also been shown to account for sporadic disease.38,39 All are missense mutations that substitute one amino acid; most are located in the globular head of the myosin heavy chain (Fig. 213-12). Like other disease alleles, myosin mutations cause hypertrophic cardiomyopathy via a dominant negative mechanism.129–131
The phenotype associated with myosin mutations is generally not quiescent. Clinically significant hypertrophy develops in virtually all genetically affected individuals by late adolescence, with markedly increased left ventricular wall thickness.41,130 The impact of myosin mutations on survival is variable, but several have been recognized to markedly reduce life expectancy.53,130,132 Individuals with either the Arg403Gln or Arg719Trp mutation have an average life expectancy of 45 years, while individuals with a Val606Met missense mutation have near-normal survival (Fig. 213-9). Although many factors are likely to influence prognosis, change in charge of the substituted amino acid appears to be one important parameter. Nonconservative β-cardiac myosin heavy chain defects have a more adverse impact on survival than conservative defects, presumably because substitutions that more severely perturb myosin structure have greater impact on function.
The considerable data about the structure and biophysical and biochemical functions of myosin molecules have helped to identify potential consequences of hypertrophic mutations. The crystal structure of the S1 fragment of the globular head of chicken skeletal muscle myosin has been solved.133 Locating hypertrophic cardiomyopathy missense mutations onto this three-dimensional structure (Fig. 213-13) reveals clustering of defects into or near four functional sites: (a) the actin binding interface; (b) the nucleotide binding site; (c) adjacent to the region connecting two reactive cysteine residues; and (d) near the interface with the essential light chain. The clinical features of disease have not been ascribed to changes in specific functional domains.
The location of hypertrophic cardiomyopathy mutations on a computer reconstruction of the 3-dimensional crystal structure of muscle myosin based on coordinates for chicken skeletal muscle myosin.110 Hypertrophic cardiomyopathy mutations (red spheres) occur throughout the myosin head domain (silver). Myosin residues that interact with actin (green) or ATP (yellow) are indicated. Hypertrophic cardiomyopathy mutations that occur in the essential and regulatory light chains (turquoise and purple, respectively) are also shown. See Color Plate 11.
The functional effects of myosin mutations on crossbridge cycling have been assessed by in vitro translocation velocities of actin filaments on surfaces bound with mutant myosin filaments.134,135 Initial data were difficult to interpret in that some defects (Arg403Gln and Tyr167Cys) inhibited actin translocation, whereas mutation Arg719Gln increased translocation velocities.135 Since low levels of β-cardiac myosin heavy chains are found in skeletal muscle, analyses of soleus muscle fibers from individuals with hypertrophic cardiomyopathy also appeared promising for understanding the biophysical properties of these mutations.136 However, isometric force generation and force-stiffness ratios in skeletal muscle fibers with different mutations also gave conflicting results: biophysical properties were reduced in muscle fibers containing the Arg403Gln mutation, but near normal in muscles bearing the Gly256Glu. Potential uncertainties associated with in vitro systems and differences that could be attributed to distinct properties of skeletal and cardiac muscle have recently been eliminated by analyses of single molecule mechanics in isolated myocytes that contain hypertrophic cardiomyopathy mutations. Studies of the biophysical properties of myocytes derived from a genetically engineered mouse that is heterozygous or homozygous for the myosin mutation Arg403Gln demonstrated higher actin-activated ATPase activity, greater force generation, and faster actin sliding.137
Not only do these data provide a potential explanation for hyperdynamic function observed clinically in patients with hypertrophic cardiomyopathy, but they also further suggest that the Arg403Gln mutation causes a gain of function. Analyses of biophysical properties of other mutations that are appropriately expressed in cardiac myocytes are needed to confirm and extend these provocative data.
The regulatory and essential myosin light chains decorate the head-rod junction of myosin heavy chains in cardiac sarcomeres. These light chains are members of the superfamily of “EF-hand” proteins, which contain a helix-loop-helix calcium-binding domain.84
The essential myosin light chain gene (MYL3; also known as alkali ventricular slow skeletal myosin light chain) is organized into seven exons (Fig. 213-14) encoded on chromosome 19p13.2-q13.2.138 Essential myosin light chains contain 166 amino acids that are expressed primarily in slow skeletal muscle and ventricles. Mutations in the essential myosin light chain gene are rare causes of hypertrophic cardiomyopathy, and account for less than 1 percent of disease. An initial report suggested some defects (Arg154His and Met149Val) produced unique morphologic changes in the myocardium: prominent midventricular and papillary muscle hypertrophy variably accompanied by intraventricular gradients.139 In addition, histologic examination of skeletal muscle biopsies from individuals with essential light chain mutations demonstrated pathologic features of primary mitochondrial disease such as ragged red fibers. Although symptoms attributed to this pathology have not been described, a subclinical skeletal myopathy appears to differentiate essential light chain mutations from other genetic etiologies of hypertrophic cardiomyopathy.
Schematic of the essential myosin light chain gene and two missense mutations that cause hypertrophic cardiomyopathy associated with subclinical skeletal myopathy.
In vitro assays of the consequence of essential light chain mutations on myosin function indicate that the Met149Val defect increases actin translocation velocities.139 Notably, the β-cardiac myosin defect (Arg719Gln) which is located in an α-helix that interfaces with the essential light chain also increases actin translocation velocities.
Atrial (MLC-2a) and ventricular slow (MLC-2s) isoforms of the regulatory myosin light chains are expressed in the myocardium; missense mutations of ventricular myosin light chains are also rare etiologies of hypertrophic cardiomyopathy.139,140 MLC-2s is a 166-amino-acid protein encoded in seven exons of the MYL2 gene (Fig. 213-15) on chromosome 12q2.140,141 Of the 5 distinct mutations identified, all are missense. As with essential light chain mutations, mid-ventricular obstruction was observed in some individuals with regulatory myosin light chains defects. In contrast, mutations Phe18Leu and Arg58Gln only caused classical morphologic features of disease.139,140
Schematic of the regulatory myosin light chain gene and the spectrum of mutations reported to cause hypertrophic cardiomyopathy.
Cardiac Myosin-Binding Protein C
Mutations in cardiac myosin-binding protein C are prevalent causes of hypertrophic cardiomyopathy; at least 20 percent of disease is attributed to these defects.41 The cardiac myosin-binding protein C gene (MYBPC3) spans 24 kb of DNA on chromosome 11p11.2 and contains 37 exons (Fig. 213-16) that encode a 1274-amino-acid (137 kDa) protein with immunoglobulin-like domains and fibronectin repeats.117,142 Cardiac myosin-binding protein C is transversely arrayed in 7 to 9 strips separated by 43-nm intervals in the C-zone of the A-bands where it binds myosin heavy chain and titin. The molecule may provide structural integrity to the sarcomere as well as modulate myosin ATPase activity and cardiac contractility when phosphorylated by adrenergic stimulation.114–117
The genomic structure of human cardiac myosin-binding protein C gene. Missense mutations, defects in splice signals (G+5 → A, G+1 → A, G+1 → T), small deletions (Δ), and insertions (Ins) have been reported to cause hypertrophic cardiomyopathy. Exons that encode sequences that interact with myosin and titin are indicated.
Many distinct types of mutations have been described within the cardiac myosin-binding protein C gene. In addition to missense mutations, defects in splice signals, small deletions, and insertions have been reported to cause hypertrophic cardiomyopathy.41,142–147 Because some mutant alleles are predicted to encode truncated and possibly unstable peptides, haploinsufficiency of cardiac myosin-binding protein C has been considered one mechanism for disease. However, immunopeptide analyses of the ventricular myocardium from one affected individual showed no diminution in the levels of cardiac myosin-binding protein C in myofibrillar fractions.145 The recent development of mice that have been engineered to express human mutations (discussed below) indicates that truncated cardiac myosin-binding protein C molecules, like other causes of hypertrophic cardiomyopathy, have a dominant negative effect on cardiac sarcomeres.
The clinical expression of either missense mutations or defects that encode truncated cardiac myosin-binding protein C peptides is similar to that observed in other genetic etiologies of hypertrophic cardiomyopathy. In contrast, the age of disease onset differs markedly (Fig. 213-17). Only half of adults under age 50 years with a cardiac myosin-binding protein C mutation had cardiac hypertrophy (wall thickness >13 mm) and in many adults disease penetrance was incomplete through age 60.41,83 Survival was generally better than that observed in hypertrophic cardiomyopathy caused by other sarcomere protein mutations (Fig. 213-9), but sudden death has been attributed to myosin-binding protein C defects.41
Age-related penetrance of hypertrophic cardiomyopathy caused by mutations in different sarcomere proteins. Solid bars indicate percentages of individuals with cardiac hypertrophy at varying ages. Significant differences in the age of penetrance of cardiac myosin-binding protein C defects (right bar) versus cardiac troponin T (center bar) or β-cardiac myosin heavy chain mutations (left bar) are indicated (†, P<0.05; §, P<0.005; ¶, P<0.0005). (From Niimura et al.41 Used with permission.)
The disease gene at one locus (chromosome 7q3) has not yet been identified.148 This locus accounts for an unusual phenotype in which both hypertrophic cardiomyopathy and preexcitation (Wolff-Parkinson-White syndrome) segregate as an autosomal dominant trait. The natural history of disease in some affected individuals also includes progressive conduction system disease, characterized by marked bradycardia and variable degrees of atrioventricular block.148,149
In summary, more than 100 mutations in genes encoding sarcomere proteins have been identified to cause familial and sporadic cases of hypertrophic cardiomyopathy. These defects are often family specific (“private”) and, to date, compilation of the full set of gene mutations that cause hypertrophic heart disease remains a work in progress. Clinical findings associated with distinct genetic etiologies indicate that onset, severity, and morphology of hypertrophy, as well as prognosis, are all influenced by genotype. The mechanism by which hypertrophic mutations cause disease appears to be through their dominant negative impact on sarcomere function. Neither genetic studies nor the limited analyses of human cardiac tissues indicate changes in the stoichiometry of sarcomere components. Many important questions are posed by these findings: (a) Why do some sarcomere protein mutations cause more severe disease than others? (b) Why do individuals with the same mutation have a wide range of clinical features? (c) How does sarcomere dysfunction lead to myocyte hypertrophy and myocyte death? The development of mice that carry germline mutations that cause hypertrophic cardiomyopathy in humans provides the opportunity to answer these and other important questions.