Why the study?
The exon13_15dup variant is the most frequent familial hypercholesterolemia-causing variant in Chile, but its functional impact is poorly understood.
Does the LDLR exon13_15dup variant alter LDLR expression, localization, and LDL uptake in patient-derived macrophages compared to wild-type?
Does the LDLR exon13_15dup variant alter LDLR expression, localization, and LDL uptake in patient-derived macrophages compared to wild-type?
Effect estimate: p<0.0001 for % LDLR-positive cells; LDL-FITC uptake 418.7 ± 269.4 vs. 928 ± 135 in control, p=0.043
Absolute Event Rate: 97.5% vs 13.9%
p-value: p<0.0001 for LDLR expression; p=0.043 for LDL uptake
The LDLR exon13_15dup variant causes defective LDL internalization despite increased receptor synthesis, providing functional evidence to classify it as pathogenic for familial hypercholesterolemia.
Background Familial hypercholesterolemia (FH) is an inherited semidominant disorder characterized by high plasma cholesterol levels and increased risk of premature cardiovascular disease. More than 3,000 low-density lipoprotein receptor (LDLR) variants have been identified, most lack functional evidence to determine their pathogenicity. One of them is the exon13_15dup, the most frequent FH-causing variant in Chile. However, its functional impact is poorly understood. Objective To determine the functional impact of the exon13_15dup variant in the LDLR, in familial hypercholesterolemia patients. Methods Three heterozygous carriers of an exon 13–15 duplication and five wild type subjects were recruited. The peripheral blood mononuclear cells were isolated and differentiated to macrophages. The LDLR expression levels on the cell membrane were evaluated by flow cytometry, subcellular localization by confocal microscopy and LDL incorporation by LDL-FITC uptake assays. Results The exon13_15dup variant leads to significantly increased cell-surface LDLR expression and enhanced localization in the endoplasmic reticulum. This results in a reduced capacity for LDL uptake in patient cells, with principal component analysis highlighting distinct differences in LDLR localization compared to wild-type samples. Conclusions The functional analysis showed that the mutation affects the proper transport and function of LDLR, resulting in a dysfunctional protein that cannot effectively internalize LDL.
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Martínez et al. (2026) studied Heterozygous carriers of LDLR exon13_15 duplication associated familial hypercholesterolemia and wild-type controls (n=8). Exon 13–15 duplication variant in LDLR gene vs. Wild-type LDLR was evaluated on LDLR cell-surface expression, subcellular localization, and LDL uptake in PBMC-derived macrophages (p<0.0001 for % LDLR-positive cells; LDL-FITC uptake 418.7 ± 269.4 vs. 928 ± 135 in control, p=0.043, p=p<0.0001 for LDLR expression; p=0.043 for LDL uptake).
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