A novel indel variant in LDLR responsible for familial hypercholesterolemia in a Chinese family.

Hongyan Shu,Yangang Wang,Wei Zhang,Yujie Deng,Jingwei Chi,Jing Li,Wenshan Lv,Xu Hou,Jie Wang,Hiroyoshi Ariga

doi:10.1371/journal.pone.0189316

Abstract

Familial hypercholesterolemia (FH) is an inherited disorder characterized by elevation of serum cholesterol bound to low-density lipoprotein. Mutations in LDLR are the major factors responsible for FH. In this study, we recruited a four-generation Chinese family with FH and identified the clinical features of hypercholesterolemia. All affected individuals shared a novel indel mutation (c.1885_1889delinsGATCATCAACC) in exon 13 of LDLR. The mutation segregated with the hypercholesterolemia phenotype in the family. To analyze the function of the indel, we established stable clones of mutant and wild-type LDLR in Hep G2 cells. The mutant LDLR was retained in the endoplasmic reticulum (ER) and failed to glycosylate via the Golgi. Moreover, the membrane LDLR was reduced and lost the ability to take up LDL. Our data also expand the spectrum of known LDLR mutations.

Highlights

Familial hypercholesterolemia (FH, MIM 143890) is an inherited disorder characterized by elevated serum low-density lipoprotein (LDL) cholesterol levels, which result in excess deposition of cholesterol in tissues, leading to accelerated atherosclerosis and increased risk of premature coronary heart disease [1]
Our findings suggest that the mutant low-density lipoprotein receptor (LDLR) could not be glycosylated in the Golgi apparatus and that it was retained in the endoplasmic reticulum (ER)
Mutations in LDLR are the major causes of FH [15, 16]

Summary

Introduction

Familial hypercholesterolemia (FH, MIM 143890) is an inherited disorder characterized by elevated serum low-density lipoprotein (LDL) cholesterol levels, which result in excess deposition of cholesterol in tissues, leading to accelerated atherosclerosis and increased risk of premature coronary heart disease [1]. FH is primarily an autosomal dominant disorder, commonly caused by the mutations in the low-density lipoprotein receptor (LDLR), its ligand apoB (APOB), or proprotein convertase subtilisin–kexin type 9 (PCSK9) genes [2,3,4]. The apolipoprotein E (AOPE) mutation was found to be associated with dominant FH [5, 6]. An autosomal recessive form of FH usually is caused by loss-of-function mutations in LDLRAP1, which encodes a protein required for clathrin-mediated internalization of the LDL receptor [7]. Approximately 85% of males and 50% of females with FH will suffer a coronary event before they reach 65 years old [9]

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Conclusion