Pharmacogenetic aspects in familial hypercholesterolemia with the special focus on FHMarburg (FH p.W556R)

Juergen R Schaefer,Alexander Sattler,Bilgen Kurt,Günter Klaus,Muhidien Soufi

doi:10.1007/s11789-012-0041-y

Juergen R Schaefer, Alexander Sattler + Show 3 more

Open Access

https://doi.org/10.1007/s11789-012-0041-y

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Abstract

ObjectiveFamilial hypercholesterolemia (FH) is an autosomal dominant inherited disorder caused by mutations in the low density lipoprotein receptor (LDLR) gene. FH is characterized by elevated plasma LDL cholesterol, premature atherosclerosis, and a high risk of premature myocardial infarction. In general, mutations within LDLR gene can cause five different classes of defects, namely: class I defect: no LDLR synthesis; class II defect: no LDLR transport; class III defect: no low density lipoprotein (LDL) to LDLR binding; class IV defect: no LDLR/LDL internalization; and class V defect: no LDLR recycling. One might expect that both the class of LDLR defect as well as the precise mutation influences the severity of hypercholesterolemia on one hand and the response on drug treatment on the other. To clarify this question we studied the effect of the LDLR mutation p.W556R in two heterozygote subjects.ResultsWe found that two heterozygote FH patients with the LDLR mutation p.W556R causing a class II LDLR defect (transport defective LDLR) respond exceedingly well to the treatment with simvastatin 40 mg/ezetimibe 10 mg. There was a LDL cholesterol decrease of 55 and 64%, respectively. In contrast, two affected homozygote p.W556R FH patients, in the mean time undergoing LDL apheresis, had no response to statin but a 15% LDL cholesterol decrease on ezetimibe monotherapy.ConclusionsThe LDLR mutation p.W556R is a frequent and severe class II defect for FH. The affected homozygote FH patients have a total loss of the functional LDLR and—as expected—do not respond on statin therapy and require LDL apheresis. In contrast, heterozygote FH patients with the same LDLR defect respond exceedingly well to standard lipid-lowering therapy, illustrating that the knowledge of the primary LDLR defect enables us to foresee the expected drug effects.

Highlights

The LDL receptor (LDLR) is an essential receptor for the uptake of low density lipoprotein (LDL) and accounts for the clearance of 70% of all plasma-circulating LDL [1]
low density lipoprotein receptor (LDLR)/LDL complexes are internalized by endocytosis, mainly in hepatocytes and ligand dischargement in the acidic environment of the endosome enables the recycling of LDL receptors for another round of LDL binding [1,2,3]
The index family is a Turkish family with two identical male twins, who are homozygote for the p.W556R LDLR mutation

Summary

Introduction

The LDL receptor (LDLR) is an essential receptor for the uptake of low density lipoprotein (LDL) and accounts for the clearance of 70% of all plasma-circulating LDL [1]. Homozygous LDLR deficiency is rare, with a frequency of 1 per million in the general population [4, 5] It is characterized by severely elevated LDL cholesterol (> 15.5 mmol/L; > 600 mg/dL). The molecular basis of FH has been elucidated by the fundamental work of Goldstein and Brown and Rader et al [6, 7] They revealed that defects of the LDL receptor are caused by mutations within the LDL receptor gene. Class IV mutations produce LDL receptors with normal transport and cell surface LDL binding but defective clustering in clathrin-coated pits for internalization. Class V mutations produce recycling defective receptors that internalize normally, but are unable to release bound ligand within the acidic environment of the endosome, and do not recycle to the cell surface [12] (Fig. 1a)

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