LDLR variants and structure-function predictions of protein models related to familial hypercholesterolemia in Vietnam

Abstract

Here, we explore familial hypercholesterolemia (FH) in the Vietnamese population which is an understudied FH ethnicity, addressing genetic and clinical variability to improve personalized healthcare. Utilizing next-generation sequencing (NGS), Multiplex ligation-dependent probe amplification (MLPA), Sanger sequencing, 103 FH cases from the Vietnam Familial Hypercholesterolemia (VINAFH) Program were analyzed, identifying 21 low-density lipoprotein receptor (LDLR) variants in 39.8 % of the patients, including 3 novel variants. Advanced computational modeling was used to obtain insights into the biological impact of these mutations. Most variants (81 %) were located in ligand-binding and Epidermal growth factor (EGF) homology domains, critical for LDLR-LDL binding and subsequent clearance. Disruptive mutations in these domains (e.g., Gln660Ter, Cys104Tyr, Cys318Arg), impaired LDLR function by destabilizing protein structure, reducing solvent-accessible surface area, and increasing root-mean-square deviation (RMSD) values, which weakened receptor-ligand interactions, leading to elevated plasma LDL-C levels. Notably, Asp227Glu enhanced stability without functional impairment, indicating mutation-specific effects. Mutations in transmembrane and cytoplasmic domains, such as Val797Met and Gly844Ser, disrupted intracellular signaling and receptor recycling, further compromising LDL clearance. Molecular dynamics simulations revealed dynamic instabilities in mutants carrying Ser586Pro and His583Tyr, linking structural flexibility and misfolding to impaired LDLR-LDL binding and trafficking (critical processes in cholesterol homeostasis). We established genotype-phenotype relationships, with homozygous FH (HoFH) and compound heterozygous FH (cHeFH) patients exhibiting more severe symptoms, including significantly higher LDL-C levels and premature atherosclerotic cardiovascular disease (ASCVD), compared to heterozygous FH (HeFH) patients. HoFH patients showed average LDL-Cholesterol (LDL-C) levels (14.83 mmol/L), consistent with severe receptor dysfunction. Variability in plasma LDL-C levels among mutation carriers and non-carriers highlights population-specific clinical diversity and suggests influence of genetic and non-genetic factors.