Abstract

Mutations in the low-density lipoprotein receptor (LDLR), which cause familial hypercholesterolemia (FH), present a variable clinical FH phenotype. To date, over 1600 FH-causing mutations have been found worldwide. The aim of this study was to investigate the structure–function relationships of LDLR mutations by using homology modeling. Structural analysis of 36 missense mutations of known receptor activity (33 severe, 1 mild, and 2 non-pathogenic phenotypes) using sequence comparison and homology modeling was performed. Severe phenotypes had less than 2% to 32% of residual LDLR activity. Mild phenotypes had 76–92% of residual LDLR activity. Finally, non-pathogenic phenotypes had normal residual LDLR activity. Sequence comparisons showed that most of the severe phenotypes were located within the fully conserved residues of LDLR, while most of the mild and non-pathogenic phenotypes were located within the poorly conserved residues. Homology modeling demonstrated several phenomena for severe phenotypes: disruption of disulfide bond formation, disturbance of the calcium binding sites, and perturbation of LDLR hydrophobic conserved packing. In contrast, mild and non-pathogenic phenotypes did not disturb the critical region of LDLR. In addition, the root mean square deviation (RMSD) values of severe phenotype tended to be higher than the mild and non-pathogenic phenotypes, and the mean of solvent accessible surface area (ASA) of the residues in wild type structure for the severe phenotype was lower than mild and non-pathogenic phenotypes. These findings provide a better understanding in the structure–function relationships of LDLR mutations and may be useful in predicting FH severity based on future genotyping.