Two novel D151Y and M391T LDLR mutations causing LDLR transport defects in Thai patients with familial hypercholesterolemia.

Background: Familial hypercholesterolemia (FH) is an autosomal dominant disorder caused by mutations in the low density lipoprotein receptor (LDLR) gene. Two novel LDLR mutations, D151Y and M391T, had been previously identified in unrelated Thai patients with heterozygous FH. To confirm that these mutations cause FH, the functional characteristics of D151Y and M391T, which are located in the fourth cysteine repeat of the ligand-binding domain and in the sixth YWTD repeat of the epidermal growth factor precursor homology domain, respectively, were studied.

Methods: CHO-ldlA7 cells were transfected with wild type and mutant LDLR cDNAs. Thereafter, the localization, expression, and ability of LDL uptake of LDLR were evaluated by confocal laser scanning microscope (CLSM), and flow cytometry.

Results: CLSM revealed both D151Y and M391T LDLR were partially retained in the endoplasmic reticulum, with the remaining residual activity observed by LDL uptake. Similarly, flow cytometric analysis showed a significant reduction of LDLR expression to 18% and 38% and of LDL uptake to 15% and 71% in D151Y and M391T LDLR, respectively.

Conclusions: The transport defect of LDLR contributes to the pathology of FH. These data are useful for an insight inspires the development of novel lipid-lowering drugs with beneficial therapeutic value.