International Journal of Molecular Medical Science, 2025, Vol.15, No.1, 42-53 http://medscipublisher.com/index.php/ijmms 46 4.3 Involvement of metabolic pathways Metabolic pathways are also significantly affected by gene mutations in FHH. Mutations in the gamma(2) subunit of AMP-Activated Protein Kinase (AMPK) have been linked to familial hypertrophic cardiomyopathy, highlighting the role of energy compromise in disease pathogenesis. These mutations result in inefficient ATP use, leading to energy depletion and myocardial dysfunction (Blair et al., 2001). Additionally, mutations in the cardiac troponin I (CTnI) gene increase Ca2+ sensitivity, altering myocardial energy metabolism by reducing fatty acid oxidation and enhancing glucose utilization. This metabolic shift contributes to the progression of hypertrophic cardiomyopathy by increasing energy consumption and altering the balance between glucose oxidation and glycolysis (Wu et al., 2012). 5 Methods for Detecting FHH-Related Gene Mutations 5.1 Genomic sequencing technologies Genomic sequencing technologies have revolutionized the detection of gene mutations associated with Familial Hypertensive Heart disease (FHH). Next-Generation Sequencing (NGS) is a prominent method, allowing for comprehensive analysis of multiple genes simultaneously. For instance, targeted NGS has been employed to screen for variants in genes such as LDLR, APOB, and PCSK9, which are implicated in familial hypercholesterolemia, a condition closely related to FHH (Al-Allaf et al., 2015; Nomura et al., 2018). This method is efficient and cost-effective, providing high sensitivity and specificity in detecting pathogenic variants (Martin et al., 2016; Zhao et al., 2019). Additionally, Whole-Genome Sequencing (WGS) and whole-exome sequencing (WES) are utilized to identify novel mutations and rare variants that may contribute to FHH (Soubrier et al., 2013). 5.2 Single-cell sequencing techniques Single-cell sequencing techniques offer a granular view of genetic variations at the cellular level, which is crucial for understanding the heterogeneity of FHH. These techniques enable the analysis of gene expression and mutation profiles in individual cells, providing insights into the cellular mechanisms underlying the disease. For example, single-cell RNA sequencing (scRNA-seq) can identify differential gene expression patterns in cardiomyocytes, which may reveal novel therapeutic targets (Mademont-Soler et al., 2017). This approach is particularly useful in studying the genetic mosaicism and clonal evolution in FHH, offering a more detailed understanding of the disease pathology (Soubrier et al., 2013). 5.3 Functional validation experiments Functional validation experiments are essential to confirm the pathogenicity of identified genetic variants. These experiments often involve in vitro and in vivo models to assess the impact of mutations on gene function and cellular processes. For instance, site-directed mutagenesis and CRISPR-Cas9 gene editing are used to introduce specific mutations into cell lines or animal models, followed by phenotypic analysis to observe the resultant effects (Versmissen et al., 2014). Additionally, biochemical assays and protein interaction studies can elucidate the functional consequences of mutations in key proteins involved in FHH, such as the beta-myosin heavy chain. These experiments are critical for translating genetic findings into clinical applications and developing targeted therapies. 6 Clinical Significance and Therapeutic Potential of FHH 6.1 Mutated genes as biomarkers for disease prediction Mutations in specific genes have been identified as significant biomarkers for predicting Familial Hypertensive Heart Disease (FHH). For instance, mutations in the beta-Myosin Heavy chain gene (MYH7) have been linked to Familial Hypertrophic Cardiomyopathy (FHC), a condition closely related to FHH. These mutations, such as 403Arg-->Leu and 403Arg-->Trp, can help identify affected individuals and carriers, providing a basis for early diagnosis and intervention. Similarly, mutations in the TPM1 gene have been associated with hypertrophic cardiomyopathy, indicating their potential as biomarkers for FHH (Carlus et al., 2020). The identification of these mutations through genetic screening can facilitate early detection and management of the disease, potentially reducing the incidence of severe cardiac events.
RkJQdWJsaXNoZXIy MjQ4ODYzNA==