Phenotypic and molecular characterization of the exon 13-15 duplication in LDLR: Implications for familial hypercholesterolemia.

Background: Familial hypercholesterolemia (FH) is an inherited disorder characterized by elevated levels of low-density lipoprotein (LDL) cholesterol, significantly increasing the risk of premature cardiovascular disease. Major rearrangements were among the first mutations identified in the low-density lipoprotein receptor (LDLR) gene and currently comprise approximately 10% of FH-causing variants. One of them is the exon13_15dup. However, the impact on the structure and function of the LDLR is poorly understood.

Objective: To determine the structural and functional impact of the exon13_15dup variant in the LDLR gene in FH patients.

Methods: The RNA extracted from CD14+ macrophage differentiation was obtained from non-consanguineous index cases carrying this mutation. Polymerase chain reaction and Sanger evaluated the junction sequence of the mutation sequenced. The obtained sequences were used to construct in silico models and perform molecular dynamics assays.

Results: The exon13_15dup variant resulted in substantial structural alterations within the LDLR, producing a truncated protein lacking both the transmembrane and cytoplasmic domains.

Conclusions: The structural changes caused by the exon13_15dup variant significantly impair the functionality of the LDLR protein, contributing to the clinical phenotype observed in patients with FH.