Soufi Muhidien, Kurt Bilgen, Schweer Horst, Sattler Alexander M, Klaus Günter, Zschocke Johannes, Schaefer Juergen R
Department of Internal Medicine, Cardiology, Philipps-University, Marburg, Germany.
Atheroscler Suppl. 2009 Dec 29;10(5):5-11. doi: 10.1016/S1567-5688(09)71802-1.
Familial 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 high risk of premature myocardial infarction. Extended work has been done to understand both, the primary genetic defect as well as the in vivo kinetic consequences of this disease. Both approaches, genetics and kinetics, are challenging but also fruitful approaches for a better understanding of this devastating disease. For this we reviewed the recent literature and used our in vitro and in vivo data on one of the most frequently occurring types of FH, the FH(Marburg) p.W556R.
To identify the primary genetic defect of the FH(Marburg) we used denaturing gradient gel electrophoresis (DGGE) mutation analysis. In vivo kinetic studies were performed in a heterozygote FH(Marburg) subject and in 5 healthy control subjects utilizing a stable isotope tracer kinetic approach with 3D-leucine.
DGGE screening of the LDLR gene identified a tryptophan (W) to arginine (R) substitution at residue 556 (p.W556R) in the fifth conserved YWTD repeat of the LDLR-beta-propeller in FH(Marburg). In vivo kinetic studies in a heterozygote FH subject for FH(Marburg) and in 5 healthy control subjects demonstrated a severe decrease in LDL FCR and a mild increase of LDL PR in FH compared to healthy controls.
The LDLR mutation p.W556R is a frequent and severe defect for FH. This defect has a major influence on the in vivo lipoprotein kinetics and lipid levels. In a heterozygote FH patient we found a dual defect for the increase in LDL cholesterol, namely a decrease in the fractional catabolic rate (FCR) of LDL but also an increase in LDL production rate (PR). By this a well defined, single genetic defect may have a series of different in vivo metabolic consequences which could be used for potential therapeutic approaches to this disease.
家族性高胆固醇血症（FH）是一种常染色体显性遗传性疾病，由低密度脂蛋白受体（LDLR）基因突变引起。FH的特征是血浆低密度脂蛋白胆固醇升高、过早发生动脉粥样硬化以及过早发生心肌梗死的高风险。为了解这种疾病的主要基因缺陷以及体内动力学后果，已经开展了大量工作。遗传学和动力学这两种方法对于更好地理解这种毁灭性疾病而言既具有挑战性，又卓有成效。为此，我们回顾了近期文献，并使用了我们关于最常见的FH类型之一——FH（马尔堡）p.W556R的体外和体内数据。
为确定FH（马尔堡）的主要基因缺陷，我们采用了变性梯度凝胶电泳（DGGE）突变分析。利用稳定同位素示踪动力学方法，采用3D-亮氨酸，在一名FH（马尔堡）杂合子受试者和5名健康对照受试者中进行了体内动力学研究。
对LDLR基因进行DGGE筛查时，在FH（马尔堡）中LDLR-β-螺旋桨的第五个保守YWTD重复序列的第556位残基处发现了色氨酸（W）到精氨酸（R）的替换（p.W556R）。在一名FH（马尔堡）杂合子受试者和5名健康对照受试者中进行的体内动力学研究表明，与健康对照相比，FH患者的LDL分解代谢率（FCR）严重降低，LDL生成率（PR）轻度升高。
LDLR突变p.W556R是FH常见且严重的缺陷。该缺陷对体内脂蛋白动力学和血脂水平有重大影响。在一名FH杂合子患者中，我们发现LDL胆固醇升高存在双重缺陷，即LDL分解代谢率（FCR）降低，但LDL生成率（PR）也升高。由此可见，一个明确的单一基因缺陷可能会产生一系列不同的体内代谢后果，这可用于针对该疾病的潜在治疗方法。
