Low Density Lipoprotein Receptor Variants in the Beta-Propeller Subdomain and Their Functional Impact

Frontiers in Genetics
Lucie DuškováLenka Fajkusová

Abstract

Background: Pathogenic variants in the low density lipoprotein receptor gene are associated with familial hypercholesterolemia. Some of these variants can result in incorrect folding of the LDLR protein, which is then accumulated inside the cell and cannot fulfill its function to internalize LDL particles. We analyzed the functional impact of 10 LDLR variants localized in the beta-propeller of epidermal growth factor precursor homology domain. The experimental part of the work was complemented by a structural analysis on the basis of 3D LDLR protein structure. Methods: T-Rex Chinese hamster ovary cells transfected with the human LDLR gene were used for live cell imaging microscopy, flow cytometry, and qRT-PCR analysis. Results: Our results showed that the analyzed LDLR protein variants can be divided into three groups. (1) The variants buried inside the 3D protein structure expressing proteins accumulated in the endoplasmic reticulum (ER) with no or reduced plasma membrane localization and LDL particle internalization, and associated with an increased gene expression of ER-resident chaperones. (2) The variants localized on the surface of 3D protein structure with slightly reduced LDLR plasma membrane localization and LDL partic...Continue Reading

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Methods Mentioned

BETA
glycosylation
protein folding
transfections
transfection
Flow
FACS
X-ray
RSA
flow cytometry

Software Mentioned

GraphPad Prism
STRIDE
MutationTaster
PolyPhen
SIFT
VMD
ClinVar

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