Understanding the Genetic and Molecular Basis of Familial Hypertrophic Cardiomyopathy and the Current Trends in Gene Therapy for Its Management

Abstract

Hypertrophic cardiomyopathy (HCM) is a genetically acquired disease of cardiac myocytes. Studies show that 70% of this disease is a result of different mutations in various sarcomere genes. This review aims to discuss several genetic mutations, epigenetic factors, and signal transduction pathways leading to the development of HCM. In addition, this article elaborates on recent advances in gene therapies and their implications for managing this condition. We start by discussing the founding mutations in HCM and their effect on power stroke generation. The less explored field of epigenetics including methylation, acetylation, and the role of different micro RNAs in the development of cardiac muscle hypertrophy has been highlighted in this article. The signal transduction pathways that lead to gene transcription, which in turn lead to increased protein synthesis of cardiac muscle fibers are elaborated. Finally, the microscopic events leading to the pathophysiologic macro events of cardiac failure, and the current experimental trials of gene therapy models, and the clustered regularly interspaced short palindromic repeats (CRISPR) type 2 system proteins, are discussed. We have concluded our discussion by emphasizing the need for more studies on epigenomics and experimental designs for gene therapy in HCM patients. This review focuses on the process of HCM from initial mutation to the development of phenotypic expression and various points of intervention in cardiac myocardial hypertrophy development.

Case Report: Novel LIM domain-binding protein 3 (LDB3) mutations associated with hypertrophic cardiomyopathy family

“…To further explore the impact of LDB3 variants (R547Q and P323S) on the occurrence of the HCM disease, we mapped the variant to the LDB3 protein structure. It is reported that variants locating within specific functional domains or protein translation modification sites can alter the protein function such as protein–ligand binding or protein–protein interaction ( 8 , 25 ). In this study, LDB3 variants (R547Q and P323S) locate in the domain of unknown function and LIM zinc-binding domain, and the two heterozygosity mutations were both yet reported previously.…”

“…In addition, genes encoding Z-disk components and Ca 2+ homeostasis factors, such as TCAP, CSRP3, ACTN2, and JPH2, can also cause HCM ( 6 ). It is well reported that most cases of HCM are caused by single-nucleotide polymorphism in genes encoding cardiac proteins ( 7 , 8 ), but the mutation-related mechanism leading to HCM is not clearly understood. However, it has been reported that genetic diversity may lead to multiple gene mutations, and these genes may jointly affect the patient phenotype ( 9 ).…”

Hypertrophic Cardiomyopathy: Genetic Foundations, Outcomes, Interconnections, and Their Modifiers

“…Modifications of gene expression in the absence of alterations in the genetic code are referred to as epigenetics [ 142 , 143 ]. Epigenetics refers to modifiers that have a role in switching genes “off” and “on” [ 142 ].…”

“…Modifications of gene expression in the absence of alterations in the genetic code are referred to as epigenetics [ 142 , 143 ]. Epigenetics refers to modifiers that have a role in switching genes “off” and “on” [ 142 ]. These changes in gene expression are mediated by DNA methylation/demethylation, histone modification, nucleosome positioning, and non-coding RNA-mediated modifications [ 142 , 143 ].…”

Genotype and Phenotype Analysis Using a Hypertrophic Cardiomyopathy-Associated Gene Panel in Turkish Cardiomyopathy Patients

“…Gene therapy is defined as the transfer of genetic material into cells for the treatment of a disease or to improve the clinical condition of a patient [7]. Since, hopeful results have been achived in the literature regarding genetherapy for the hypertrophic cardiomyopathy, It is very importent to elucidate the causative mutation of the disease [8].In the present study, 21 patients with HCM and some of their parents were evaluated via nextgeneration sequencing (NGS) using a targeted panel of 17 genes (ACTC1, CALR3, DES, LAMP2, MYBPC3, MYH6, MYH7, MYL2, MYL3, PRKAG2, SLC25A4, TNNI3, TNNT2, RAF1, TPM1, TNNC1, TTN). This study aims to provide a genetic diagnosis of the patients in this cohort and discusses genotype-phenotype correlations of the patients according to the literature.…”