The MYBPC3 encodes the cardiac isoform of myosin-binding protein C (cMBP-C). This gene spans a 3.7 kb DNA sequence and contains 34 coding elements, ultimately forming 35 exons. These exons are transcribed to produce a 3824 bp transcript. cMBP-C, a member of the intracellular immunoglobulin superfamily, is encoded by the MYBPC1 and MYBPC2 in skeletal muscle and by the MYBPC3 in the heart. Its structure includes eight immunoglobulin-like domains (C0, C1, C2, C3, C4, C5, C8, C10) and three fibronectin type III domains (C6, C7, C9) [16, 17]. The core function of cMBP-C is to precisely regulate cross-bridge recycling in cardiomyocytes through phosphorylation and interaction with other factors, thereby contributing to the assembly of myocardial heavy chains. This regulation is crucial for ensuring that the heart muscle contracts and relaxes properly. Additionally, cMBP-C modulates the sensitivity of fibrin protein to calcium ions, which in turn affects the contractile performance of the myocardium. This discovery offers a new perspective for understanding the mechanisms underlying myocardial contraction [18].

Since the MYBPC3 was recognized by the scientific community as the main causative gene of HCM in 1995, a large number of studies have focused on this gene and its related mutations. To date, more than 600 mutations related to the MYBPC3 have been discovered, and these mutations account for approximately 35% of mutation-positive HCM patients. This finding further solidifies MYBPC3’s status as a major causative gene in HCM [19, 20, 21]. Among the known MYBPC3 mutations, more than 60% are truncating mutations, including nonsense mutations, insertions or deletions, splicing or branch point mutations, and the MYBPC3 is tolerant to missense and LoF mutations (LOUEF: 0.96). Truncating mutations often activate nonsense-mediated decay (NMD) and the ubiquitin-proteasome system (UPS), leading to haplodeficiency of the cMBP-C, the production of toxic peptides, and the COOH-terminal truncation of cMBP-C, which in turn causes myosotrophy (Fig. 2). The deletion of the protein or its binding site causes abnormalities in the structure and function of myosin, ultimately leading to haploid protein deficiency. Haploid gene defects are the predominant manifestation of heterozygous deletion mutations, and most MYBPC3-related HCM mutations are heterozygous [22, 23].

Fig. 2.

MYBPC3 encodes cardiac myosin binding protein-C, which is a key structural protein of the myocardium and plays an important role in the relaxation and contraction of the myocardium. When MYBPC3 mutates, it produces a truncated protein product that activates the UPS system and ultimately leads to HCM. cMBP-C, cardiac myosin binding protein-C; Ub, ubiquitin; E1, ubiquitin-activating enzyme; E2, ubiquitin-conjugating enzyme; DUB, deubiquitinating enzymes; UPS, ubiquitin-proteasome system; P, phosphonates. Created by Adobe Illustrator (Adobe Inc., San Jose, CA, USA).

Clinical phenotypes caused by MYBPC3 mutations often share some common characteristics: disease onset usually occurs after middle age, cardiac hypertrophy is relatively low, and disease progression is slow. Clinically, truncating mutations and double mutations in the MYBPC3 often lead to more severe clinical phenotypes. In addition to changes in cMBP-C composition that can lead to myasthenia gravis and peptide toxicity, its function is also regulated by a variety of post-translational modifications, including phosphorylation, acetylation, citrullination, and oxidation. Compensatory slowing of calcium processing preserves contractile parameters, whereas faster sarcomere dynamics reduce myocardial contractility [24]. At present, at least three phosphorylation sites have been found to be located in the molecular structure of cMBP-C and targeted by protein kinases. These sites begin at Ser282, which acts as a switch to make Ser273 and Ser302 more susceptible to phosphorylation. Currently known protein kinases that can phosphorylate MBP-C include protein kinase A (PKA), Ca²⁺/calmodulin-dependent kinase II, p90 ribosomal S6 kinase, protein kinase D and protein kinase C, etc. [25]. Research shows that MYBPC3 therapy has the potential to restore MBP levels, with the goal of preventing heart failure and reducing mortality in MYBPC3-related cardiomyopathy. Each genetic mutation has its own unique clinical manifestations. For example, men with the MYBPC3 c.2149-1G$>$A splice variant have an earlier onset of HCM and a higher penetration rate than women. When the pathogenicity of a mutation is confirmed, relatives carrying the mutation are eligible for surveillance to detect early signs of disease, treat it, and prevent its consequences [26]. Although understanding the causative genes of patients with HCM cannot change the current course of treatment, genetic testing can provide probands and relatives with prognostic data. Specific types of mutations can predict likely disease onset and associated clinical outcomes [27]. Through genetic screening, we can conduct regular health monitoring of young mutation carriers in the family who have not yet shown symptoms, thereby enabling early identification and intervention of potential risks. This measure is particularly important in the diagnosis and treatment of HCM. Genetic testing of HCM patients can not only reveal the genetic roots of the disease and provide important basis for the formulation of treatment plans, but also promote the development of family screening, which has far-reaching implications for the early diagnosis of family members and early intervention and treatment of mutation carriers [28].

The MYH7 is located on chromosome 14q11.2-q13 and contains 40 exons. It encodes the $\beta$-myosin heavy chain ($\beta$-MHC), which consists of 1935 amino acids and serves as the core component of ventricular myosin. The protein is composed of two heavy chains and four light chains, forming three functional regions: the head, neck, and tail, which collectively drive muscle contraction. The motor domain S1 of the head binds to actin and ATP, facilitating cardiomyocyte contraction. The tail region comprises S2 and light filament myosin, while the neck region connects the head and tail [29]. MYH7 plays a key role in the contraction and relaxation of cardiomyocytes. HCM patients with mutations in it are more likely to develop left ventricular outflow tract obstruction than those with MYBPC3 mutations. They have an earlier age of onset, high clinical phenotype penetrance, severe myocardial hypertrophy, and a high rate of sudden death, the prognosis is poor. There are currently multiple views on the pathogenesis of HCM caused by MYH7 gene mutations. These mechanisms mainly include changes in mitochondrial function, changes in muscle cell structure and contractility, and abnormalities in the regulation of ATP hydrolysis and ADP release. These changes together lead to insufficient energy supply to the ventricular myocardium, which in turn triggers hypertrophy of the ventricles or interventricular septum. Further research also revealed the important role of mitochondrial function in the pathogenesis of HCM. Metabolic disorders and mitochondrial dysfunction are common pathological features in HCM patients. Experimental data show that in a mouse model of HCM with MYH7 mutations, fibroblast growth factor 21 levels are significantly increased and the increase in mitochondrial DNA copy number is consistent with changes in mitochondrial activity and the development of cardiomyopathy [30]. In addition, missense mutations in the MYH7 can also affect the structure and function of cardiomyocytes, leading to the occurrence of HCM. Most of these mutations are located in the globular head and neck regions of the $\beta$-MHC protein, affecting binding sites with ATP, actin, and essential or regulatory light chains. Mutations may also lead to disruption of thick filament dimerization, thereby affecting myosin ATP hydrolysis and myofilament sliding [31].

The severity of HCM is closely related to the proportion of abnormal myosin in cardiomyocytes. Mutations in the MYH7 may cause disease through a dominant-negative “toxic peptide” mechanism, that is, the abnormal myosin produced by the pathogenic mutation will interfere with the normal contractile function of the sarcomere. In addition, MYH7 gene mutations may also increase the sensitivity of myofibrillar cells to Ca²⁺, leading to increased myocardial energy consumption and ventricular diastolic dysfunction, further exacerbating ventricular hypertrophy [32]. The pathogenicity of MYH7 gene mutations is closely related to its key function in cardiomyocytes. These mutations not only affect the contractile function of cardiomyocytes but may also lead to changes in a complex genetic and epigenetic background. Therefore, an in-depth study of the pathogenic mechanism of MYH7 gene mutations is of great significance for early diagnosis, precise treatment and prognosis judgment of HCM patients. It is exciting to see that significant progress has been made in the current field of gene therapy research. In particular, the combined application of gene therapy or gene editing technology and human-induced pluripotent stemcell-derived cardiomyocyte (hiPSC-CM) has opened up a new way for individualized cultivation of mature cardiomyocytes. This breakthrough technology may bring unprecedented hope for the treatment of HCM patients caused by MYH7 gene mutations.

The traditional concept is that caveolae are a rich place for intracellular signaling molecules and can form complexes to regulate ion channels, vesicle transport and signal transduction. But modern molecular biology techniques have revealed more functions of caveolae, such as maintaining cholesterol homeostasis and regulating signaling [33]. However, the regulation of cholesterol homeostasis remains controversial. Caveolae is a key characteristic protein on the caveolae membrane, which is essential for maintaining the morphology, structure and function of caveolae. It also constitutes a special subset of lipid rafts [34]. As the main component of caveolae, caveolin-3 (CAV3) was first cloned and identified in 1996. It consists of 151 amino acids and contains several independent domains: N-terminal domain (residues 1–53), CSD domain (residue 54–73), transmembrane domain (residues 74–106) and c-terminal domain (residues 107–151) [35]. Most of its mutations are concentrated in the caveolin scaffolding domain, which is involved in self-assembly and interaction with signaling molecules. Therefore, CAV3 plays an important role in cell physiology, including regulating ion channels, vesicle transport, cholesterol and calcium homeostasis, and signal transduction. It serves as a molecular chaperone and scaffold through the scaffolding domain to regulate a variety of signaling molecules.

When the CAV3 mutates, it may lead to varying degrees of lesions in skeletal muscle, myocardium and other tissues through various mechanisms. This type of disease is collectively called caveolin disease. The caveolin-3 protein encoded by the CAV3 gene is a key component of caveolae. It is expressed in cardiac muscle, skeletal muscle and smooth muscle, and interacts with a variety of molecules related to cardiac hypertrophy signals [36]. In cardiomyocytes, a variety of signaling molecules such as $\beta$2-ARs, m2-mAChR and their related G protein subunits, adenylyl cyclase isoforms, G protein-coupled receptor kinase family members (such as GRK2) and catalytic subunit of protein kinase A, etc. will accumulate in caveolae when cells are in a steady state or activated state. This indicates that caveolae are not only a physical gathering place for signaling molecules, but also serve as a scaffold for preassembled membrane-bound oligomer complexes, providing a platform for rapid coupling between receptors and effectors. This rapid coupling process is critical for sympathetic regulation of cardiomyocyte function, ensuring that cardiomyocytes can rapidly respond and adapt to various physiological and pathological conditions [37].

It is worth noting that the distribution of $\alpha$1-AR in the plasma membrane is not random, but tends to accumulate in caveolae. This means that caveolae may be a key microdomain of $\alpha$1-AR signaling, which can promote the interaction between $\alpha$1-AR and other signaling molecules, thereby regulating the function and response of cardiomyocytes. When $\alpha$1-AR signaling is enhanced, it may accelerate the development of cardiac hypertrophy. As the main component of caveolin, its reduced inhibitory effect on growth factor signaling may also play an important role in the pathogenesis of cardiac hypertrophy. In caveolin-3-deficient transgenic mice, researchers observed that the development of hypertrophic cardiomyopathy is closely related to increased endothelial nitric oxide synthase (eNOS) activity. Myocardial contractility was enhanced in these mice, but NOS expression levels did not change. This finding suggests that loss of NOS inhibition secondary to caveolin-3 deficiency may be a key link in the pathogenesis of hypertrophic cardiomyopathy. Further research showed that the activity of NOS has a significant impact on cardiac function. eNOS and neuronal nitric oxide synthase (nNOS) are localized in caveolae and sarcoplasmic reticulum (SR) respectively, and they exert different effects on cardiac contractility. For example, knockdown of eNOS enhances myocardial contractility, whereas overexpression reduces cardiac size and decreases contractility. Of particular note, mouse hearts with moderately increased eNOS activity exhibit enhanced contractility and features of hypertrophic cardiomyopathy, whereas extremely high activation of eNOS reduces myocardial contractility and heart size [38]. In addition, the contractile response to cardiac tissue produced by exogenous nitric oxide also appears biphasic. Low levels of nitric oxide enhance myocardial contractility, while high levels have an inhibitory effect. This phenomenon further demonstrates that moderate and extremely high activation of eNOS activity have distinct effects on cardiac function [39]. CAV3 and its encoded proteins play an important role in cell signaling, ion channel regulation, and the pathogenesis of cardiomyopathy, and are of great significance for understanding these complex biological processes and treating related diseases.

The GLA is a gene in the human genome and is located on the X chromosome. The coding sequence of the GLA contains 7 exons and 6 introns, with a total length of approximately 13.5 kb. It includes the transcription start site, coding region, and termination site. This gene encodes a protein called $\alpha$-galactosidase A ($\alpha$-Gal A) [40]. $\alpha$-Gal A is an enzyme composed of 429 amino acids that catalyzes the hydrolysis of $\alpha$-galacturonide into galactose and fatty acids. This enzyme’s activity is crucial for normal metabolism and cellular function. It contains a signal peptide sequence that directs its localization to the cytoplasm, followed by post-translational modification to produce the mature $\alpha$-Gal A protein. The mature protein has an $\alpha$/$\beta$ fold structure and comprises four domains: an N-terminal $\alpha$-helical domain, a middle $\beta$-turn domain, a C-terminal $\alpha$/$\beta$ ribbon domain, and a C-terminal $\alpha$-helical domain. These domains are essential for the function and stability of $\alpha$-Gal A. Additionally, the $\alpha$-Gal A protein contains a covalently attached sugar group, which is also necessary for its stability and function.

The mature $\alpha$-Gal A enzyme is localized in the lysosomes, organelles within cells that are responsible for breaking down and degrading waste products, lipids, and proteins. Within lysosomes, the $\alpha$-Gal A enzyme binds to $\alpha$-galacturonide and catalyzes its hydrolysis, breaking it down into galactose and fatty acids. These products can then be further processed and utilized in other metabolic pathways. The enzyme normally plays a crucial role in breaking down a lipid called acylsphingosine trihexoside. However, mutations in the GLA alter the enzyme’s structure and function, impairing its ability to break down this fat. As a result, acylsphingosine trihexosylglycosides and diposylceramides accumulate in body cells, particularly in blood vessels of the skin, kidneys, heart, and nervous system, which adversely affects the normal functioning of these organs. This abnormal lipid accumulation can lead to tissue and organ damage.

In cardiac cells, this deposition leads to organelle dysfunction, intracellular metabolism and energy production are affected, and ultimately leads to cardiomyocyte hypertrophy and hyperplasia. Deposition of Gb3 leads to the formation of its metabolite lyso-Gb3 [41]. Lyso-Gb3 is a degradation product of Gb3 but also accumulates within cells. The deposition of Gb3 and lyso-Gb3 causes intracellular metabolic abnormalities and lysosomal dysfunction in cardiac cells, leading to hypertrophy, hyperplasia, and fibrosis of cardiac myocytes [42]. Gb3 and Lyso-Gb3 are deposited in various cells of the cardiovascular system, leading to various manifestations including left ventricular hypertrophy, conduction abnormalities, aortic valve and mitral valve insufficiency, etc. [43]. Gb3 is deposited in all types of cells and tissues in the heart, including cardiomyocytes, intramyocardial blood vessels (endothelial and smooth muscle cells), and conductive tissue. In addition to the mechanical effects of deposition, the accumulation of these substances can trigger secondary reactions, damaging cellular endocytosis and autophagy functions, inducing apoptosis, and disrupting mitochondrial energy production. This leads to abnormal energy metabolism and increased oxidative stress, which in turn triggers metabolic changes within cells. These alterations contribute to cellular remodeling and activate pathways that promote cellular hypertrophy. Accumulated Gb3 may also change the expression of ion channels and/or cell membrane transport, thereby changing the electrophysiological properties of cardiomyocytes, leading to an increase in myocardial conduction velocity between the atrium and ventricle, resulting in a shortened PR interval on the patient’s electrocardiogram [44]. Gb3 and Lyso-Gb3 can also serve as antigens to activate natural killer T cells, leading to chronic inflammation and autoimmune reactions, leading to pathological damage and fibrosis of cardiomyocytes, further promoting the occurrence of myocardial thickening, and ultimately leading to HCM.

The LAMP2 is a gene encoding lysosomal-associated membrane protein 2 (LAMP2). It is located on the X chromosome of the human genome and is also known as a Danon disease-related gene. LAMP2 is one of the main protein components of the lysosomal membrane. There are currently three main subtypes: LAMP2A, LAMP2B and LAMP2C [45]. Its structure includes extracellular domain, transmembrane domain and intracellular domain, which plays an important role in maintaining the structure and function of lysosome. LAMP2 forms a stable structure on the lysosomal membrane and helps maintain lysosome integrity and stability. It participates in regulating the formation, fusion and transport processes of lysosomes, ensuring the normal function of lysosomes within cells [46].

LAMP2 gene mutations can lead to defects in the autophagy function of autophagosomes, disorders in the fusion process of lysosomes and target cells, and loss of organelle motility, ultimately leading to the accumulation of autophagosomes in cardiomyocytes and the storage of glycogen in the cytoplasm [47]. LAMP2B is mainly involved in the biogenesis of lysosomes and macroautophagy, and is indispensable for the fusion of autophagosomes and lysosomes in cardiomyocytes [48]. LAMP2B is indispensable for autophagosome and lysosome fusion in cardiomyocytes. LAMP2B on the lysosomal membrane interacts with autophagy related gene 14 (ATG14) and vesicle-associated membrane protein 8 (VAMP8) through its C-terminal domain to mediate autophagosome-lysosome fusion, thereby regulating cardiomyocyte function [45]. ATG14 is an important factor in the autophagy process. It binds to the Beclin-1 complex (similar to the PI3K complex) and participates in the formation of autophagosomes and the regulation of the autophagy process. LAMP2B helps regulate the formation of autophagosomes and promotes the fusion of autophagosomes and lysosomes by binding to ATG14. VAMP8 is a vesicle-associated membrane protein that participates in the process of vesicle trafficking and fusion within cells. During the autophagy process, LAMP2B helps regulate the fusion process between autophagosomes and lysosomes through its interaction with VAMP8, promoting the degradation of the contents in autophagosomes by lysosomes. Loss of LAMP2B leads to autophagy-lysosomal maturation impairment. This dysfunction may cause the autophagic vacuoles within autophagosomes to be unable to effectively fuse with lysosomes, thereby affecting the degradation and clearance of autophagic contents [49]. Due to lysosomal dysfunction, glycogen in autophagosomes cannot be effectively degraded and cleared, resulting in the accumulation of glycogen. This accumulation of glycogen leads to metabolic disorders and energy imbalance within cardiomyocytes. Similarly, lysosomal dysfunction can also lead to the accumulation of other autophagic vacuoles in autophagosomes that cannot be effectively degraded and cleared. The accumulation of autophagic vacuoles and glycogen can lead to metabolic disorders within cardiomyocytes, including disorders of energy metabolism and disorders of waste clearance. This metabolic disorder can lead to intracellular functional abnormalities, including reduced calcium ion processing capabilities, abnormal cell signaling, etc., thereby affecting the structure and function of cardiomyocytes; triggering intracellular stress responses, including inflammatory responses, oxidative stress, etc. These stress reactions will cause the activation of intracellular biochemical pathways and promote the hypertrophy and proliferation of muscle cells; the accumulation of metabolites and waste products will increase the volume of cells and trigger a series of changes in cell signaling pathways, thereby promoting the hypertrophy of cardiomyocytes and hyperplasia. In addition, missing or dysfunctional LAMP2 can lead to obstruction of lysosomal autophagy, which in turn can lead to damage and death of cardiomyocytes, thereby causing fibrosis and granuloma formation during the repair process. These abnormal tissue repair and inflammatory responses may cause cardiac hypertrophy [49, 50, 51]. Fig. 3 shows some of the mechanisms by which LAMP2 mutations cause HCM.

Fig. 3.

LAMP2 is located on the lysosomal membrane and assists in the fusion of lysosomes and autophagosomes. The mutation leads to impairment of myocardial autophagy by reducing the fusion of lysosomes and autophagosomes, leading to glycogen accumulation and ultimately HCM. LAMP2, lysosomal-associated membrane protein 2; ATG14, autophagy-related protein 14; VAMP8, vesicle-associated membrane protein 8. Adobe Illustrator (Adobe Inc., San Jose, CA, USA).

In addition, there is increasing recognition that other rare genetic disorders may mimic the phenotypic and clinical features of HCM but are caused by mutations in different genes. Notable among these conditions are Fabry disease (an X-linked a-galactosidase deficiency with glycosphingolipid deposition), PRKAG2 syndrome (caused by mutations in the regulatory subunit of adenosine monophosphate-activated protein kinase), and LAMP2 deficiency (a lysosomal storage disorder, also known as Danon disease) [52, 53, 54, 55].

ACTC1 is responsible for encoding $\alpha$-cardiac actin, which together with tropomyosin and three types of troponins form thin contractile filaments that connect the muscle cell Z-disk to the thick filament protein myosin. The complex is mainly expressed in cardiomyocytes. ACTC1 is the only actin expressed in embryonic cardiac muscle, has a very conserved amino acid sequence, and is critical for multiple cellular functions. In addition to its classic role in muscle contraction, actin also interacts with the actin skeleton, affecting its multiple functions such as polymerization and depolymerization, thus participating in the regulation of gene transcription. Actin also maintains its normal functions such as morphological stability and division by interacting with chromatin remodeling complexes [56, 57]. Lack or mutation of ACTC1 may affect its interaction with actomyosin and binding to regulatory proteins, ultimately exhibiting embryonic lethality and myofibrillar disorganization.

Most cases of HCM are caused by mutations in genes encoding sarcomeric proteins, with less than 3% of pathogenic variants found in the sarcomeric gene ACTC1 [58]. Currently, 12 different ACTC1 mutations have been found in HCM patients. ACTC1 mutations are divided into three categories according to the position of the amino acid changes in actin: ① mutations that only affect the motor binding site of the myosin molecule are called M-type mutations, ② mutations that only affect the tropomyosin binding site, called T-class mutations, and ③ mutations that affect both myosin and tropomyosin binding sites, are called MT-class mutations [59, 60] (Table 1).

Symptoms in patients with HCM often include systolic dysfunction and restricted diastole, this may be because mutations in the ACTC1 associated with HCM alter the structure and function of cardiac actin, thereby affecting myocardial function [61]. A study has found that a non-synonymous mutation (p.Gly247Asp or:G247D) in the ACTC1 leads to increased cardiomyocyte apoptosis and sarcomeric disorganization, both of which have deleterious effects on contractile function [62]. Studies have found that sarcomeric protein mutations cause intrinsic abnormalities in myofibrillar structure and function. These abnormalities jointly drive invasive structures at the cellular and extracellular levels by interfering with the excitation-contraction coupling process, cardiomyocyte energy metabolism, cardiomyocyte signaling, and other mechanisms. Remodeling, which in turn impairs myocardial systolic and diastolic function, leads to the common occurrence of progressive left ventricular dysfunction in HCM [63, 64]. The specific mechanism by which ACTC1 mutations cause HCM remains unclear. ACTC1 mutations lead to increased myocardial cell apoptosis and abnormal sarcomeres, resulting in abnormal myocardial systolic and diastolic function, which in turn leads to abnormal cardiac morphology and hemodynamic disorders. This may be a potential mechanism for continued research.

TNNT2 is located on chromosome 1 (1q32), encoding cardiac troponin T2 (TnT). It mainly regulates actin filament function by binding calcium ions and is crucial for human cardiac muscle contraction and relaxation [65]. TnT interacts with the other two troponin subunits, troponin T (TnT) and troponin C (TnC), through the C-terminus to form a stable trimer core, and the N-terminus interacts with actin filaments. Binding at specific sites anchors the troponin complex to the myofilaments and moves as the muscle contracts and relaxes. 2%–5% of HCM patients are caused by pathogenic mutations in this gene, and abnormal N-terminal splicing and TnT point mutations are possible causes. Abnormal splicing of N-terminal exon 5 can affect the interaction between cTnT and tropomyosin, interfere with the calcium sensitivity of myofibrils, thereby affecting cardiac contraction, ultimately leading to cardiac hypertrophy and HCM [66, 67]. More than ten TNNT2 single mutations causing HCM have been found, such as Ile79Asn, Glu244Asp, etc., but the specific mechanism is still not completely clear. Homozygous mutations are very rare and usually have a more severe phenotype than heterozygous mutations in a gene dose-dependent manner [68, 69]. A homozygous mutation K280N (c.804G$>$T) can 100% cause changes in TnT, leading to an acceleration of the shedding rate of sarcomere cross-bridges and an increase in the energy cost of tension, supporting the pathogenesis of cardiomyopathy caused by inefficient utilization of ATP by myofilaments [70]. Some types of TNNT2 mutations and corresponding mechanisms are summarized in Table 2 (Ref. [71, 72, 73, 74, 75, 76, 77, 78, 79, 80]).

A study has shown that by replacing mutated TnT with wild-type TnT, the rate constants of tension and isometric relaxation generated after maximum Ca²⁺ activation can be reduced, reducing the tension cost to unmutated control values, suggesting that the direct effect of the mutant protein can be reversed. Therefore, the introduction of normal protein remission may be a potential therapeutic strategy to treat this type of HCM patients [70]. Table 3 summarizes all the gene types, functions and phenotypic characteristics mentioned above.