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(Circulation Research. 2008;103:1280.)
© 2008 American Heart Association, Inc.

Molecular Medicine

Mutation in EGFP Domain of LDL Receptor-Related Protein 6 Impairs Cellular LDL Clearance

Wenzhong Liu, Sheida Mani, Nicole R. Davis, Nizal Sarrafzadegan, Paula B. Kavathas, Arya Mani

From the Departments of Internal Medicine (W.L., A.M.), Therapeutic Radiology (S.M.), Psychiatry (N.R.D.), Laboratory Medicine, Genetics, and Immunobiology (P.B.K.), Yale University School of Medicine, New Haven, Conn; and Isfahan University of Medical Sciences (N.S.), Isfahan, Iran.

Correspondence to Arya Mani, Yale University School of Medicine, FMP3, 333 Cedar Street, New Haven, CT 06520. E-mail arya.mani{at}yale.edu

Mutation in the EGFP domain of LDL receptor-related protein 6 (LRP6_R611C) is associated with hypercholesterolemia and early-onset atherosclerosis, but the mechanism by which it causes disease is not known. Cholesterol uptake was examined in cells from LRP6^+/– mice and LRP6_R611C mutation carriers. Splenic B cells of LRP6^+/– mice have significantly lower LRP6 expression and low-density lipoprotein (LDL) uptake than those of the wild-type littermates. Although similar levels of total LRP6 were found in lymphoblastoid cells (LCLs) of LRP6_R611C mutation carriers and those of the unaffected family member, LDL uptake was significantly lower in the mutant cells. Mutant and wild-type receptors show similar affinities for apolipoprotein B at neutral pH. LRP6 colocalized with LDL and was coimmunoprecipitated with NPC1 (Niemann–Pick disease type C1), an endocytic regulator of LDL trafficking. However, the cellular localization of LRP6 in the mutant cells shifted from cell surface to late endosomes/lysosomes. Plasma membrane expression levels of LRP6_R611C was lower compared to wild-type receptor and declined to a greater extent in LDL-rich medium. Further examinations revealed lower efficacy of apolipoprotein B dissociation from LRP6_R611C compared to wild-type receptor at an acidic pH. These studies identify LRP6 as a receptor for LDL endocytosis and imply that R611C mutation results in reduced LRP6 membrane expression and decreased LDL clearance. Based on our findings, we conclude that the increased affinity of the mutant receptor for LDL in acidic pH leads to their impaired dissociation in late endosomes, which compromises their recycling to the plasma membrane.

Key Words: atherosclerosis • cholesterol • hypercholesterolemia • receptors • genetics

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