International Journal of Molecular Medical Science, 2025, Vol.15, No.1, 42-53 http://medscipublisher.com/index.php/ijmms 43 mutation data associated with FHH to provide a comprehensive understanding of the genetic background of the disease. The study also seeks to identify gaps in current research and propose future directions that could improve the diagnosis and treatment of patients with familial hypertensive heart disease. 2 Genetic Basis of Familial Hypertensive Heart Disease 2.1 Major genetic pathways and mechanisms Familial hypertensive heart disease is influenced by several key genetic pathways that regulate blood pressure and cardiac function. The Renin-Angiotensin-Aldosterone System (RAAS) is a critical pathway, with genetic variants in this system significantly impacting blood pressure regulation and cardiovascular health (Lip and Padmanabhan, 2020). Additionally, calcium signaling pathways play a central role, particularly through genes such as CACNA1D, which have been associated with blood pressure regulation in Genome-Wide Association Studies (GWAS) (Lu et al., 2015). Molecular mechanisms by which gene mutations affect cardiac structure and function include the inefficient use of ATP, as seen in mutations of the PRKAG2 gene, which encodes the gamma(2) subunit of AMP-Activated Protein Kinase (AMPK). These mutations lead to energy compromise, a central pathogenic mechanism in Hypertrophic Cardiomyopathy (HCM) (Blair et al., 2001). Furthermore, mutations in the CUL3 gene, which encodes a scaffold protein in an E3 ubiquitin ligase complex, result in the accumulation of substrates like WNK kinase, affecting renal NaCl cotransporter activity and vascular tone, thereby contributing to hypertension (Figure 1) (Maeoka et al., 2023). Figure 1 Combined reduction of CUL3 (Cullin 3) and KLHL3 (Kelch-like 3) is a central renal mechanism in familial hyperkalemic hypertension (FHHt) (Adopted from Maeoka et al., 2023) Image caption: Wild-type, under normal conditions, CUL3 and KLHL3 mediate WNK (with-no-lysine [K]) 4 degradation. Cycling of NEDD8 (N8; Neural precursor cell expressed developmentally downregulated-8) conjugation (neddylation) by NAE1 (NEDD8-activating enzyme E1) and removal (deneddylation) by CSN5 (constitutive photomorphogenesis 9 signalosome 5) minimizes degradation of KLHL3 by wild type (WT) CUL3. FHHt models, in CUL3 heterozygous mice expressing CUL3-Δ9 from a transgene (Cul3+/−/Δ9) and knockin mice with exon 9 deletion (CUL3WT/Δex9) CUL3-Δ9 cannot interact with CSN5, resulting in hyperneddylation. This causes CUL3-Δ9 autoubiquitination and degradation and promotes KLHL3 degradation. WNK4 accumulates causing excessive NaCl cotransporter (NCC) phosphorylation (pNCC) and activation, leading to FHHt. Cul3+/−/Klhl3+/− micewith lower CUL3 and KLHL3 display higher WNK4 and pNCC and an FHHt-like phenotype (Adopted from Maeoka et al., 2023)
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