Mott S, Yu L, Marcil M, Boucher B, Rondeau C, Genest J
Cardiovascular Genetics Laboratory, McGill University Health Center, Royal Victoria Hospital, 686 Pine Avenue West, Québec, 3A 1A1, Montréal, Canada.
Atherosclerosis. 2000 Oct;152(2):457-68. doi: 10.1016/s0021-9150(99)00498-0.
High density lipoproteins (HDL) are complex lipoprotein particles involved in reverse cholesterol (C) transport and are negatively associated with the risk for coronary artery disease (CAD). We have described a disorder of familial HDL deficiency (FHD) due to abnormal cellular cholesterol efflux. In the present study, we investigated cellular cholesterol efflux on skin fibroblast from 15 probands with moderate to severe hypoalphalipoproteinemia, including one subject with Tangier disease (TD). We performed family studies on eight of these probands (269 individuals) with familial hypoalphalipoproteinemia (defined as a HDL-C <5th%, and with no known cause of HDL deficiency). We have previously shown that four of our FHD patients and patients with TD have mutations at the ABC1 gene, demonstrating that FHD is a heterozygous form of TD.
On each subject, we carried out detailed biochemical analysis and determined apoA-I-mediated cellular cholesterol efflux using 3H-cholesterol labeled skin fibroblasts from study subjects compared with controls. TD has also been associated with abnormal cellular cholesterol efflux. Cell fusion experiments with polyethylene glycol (PEG) were carried out with fibroblasts from a subject with TD and one with FHD in order to determine whether the Tangier cells can complement the FHD defect. In all subjects with a reduced cellular cholesterol efflux, exons of the ABCA1 gene were sequenced.
Familial forms of HDL deficiency, defined as HDL-C levels <5th percentile, are a heterogeneous group of lipoprotein disorders. A reduced cellular cholesterol efflux has been identified in eight subjects from seven kindred (7/14 or 50% of probands tested), being reduced by a mean 59% of controls (range 49-63%). In four of these subjects, a mutation at the ABCA1 gene locus was identified. In three other subjects an efflux defect was idenfified but no critical mutation at the ABCA1 gene locus has been identified. In the remaining subjects, (7/14), no efflux defect was identified. Complementation studies reveal that the FHD defect is not corrected by Tangier cells, confirming that FHD and TD represent a spectrum of the same genetic defect.
Familial hypoalphalipoproteinemia syndromes are phenotypically heterogeneous; one form is associated with abnormal cellular cholesterol efflux caused by heterozygous mutations at the ABCA1 gene, that defines familial HDL Deficiency while homozygous mutations or compound heterozygocity causes TD. Other forms are primary hypoalphalipoproteinemia of unknown cause, while the remaining cases are associated with hypertriglyceridemia with or without elevated apoB levels. We conclude that a cellular cholesterol defect is a relatively frequent cause of familial HDL deficiency and that a mutation at the ABCA1 gene can be identified in half of these patients.
高密度脂蛋白（HDL）是参与逆向胆固醇（C）转运的复杂脂蛋白颗粒，与冠状动脉疾病（CAD）风险呈负相关。我们曾描述过一种由于细胞胆固醇流出异常导致的家族性HDL缺乏症（FHD）。在本研究中，我们调查了15名中度至重度低α脂蛋白血症先证者（包括1名Tangier病（TD）患者）皮肤成纤维细胞的细胞胆固醇流出情况。我们对其中8名先证者（269名个体）进行了家族性低α脂蛋白血症（定义为HDL-C<第5百分位数且无已知HDL缺乏原因）的家族研究。我们之前已表明，我们的4名FHD患者和TD患者在ABC1基因存在突变，证明FHD是TD的杂合形式。
对每个受试者进行详细的生化分析，并使用来自研究受试者的3H-胆固醇标记皮肤成纤维细胞与对照相比，测定载脂蛋白A-I介导的细胞胆固醇流出。TD也与细胞胆固醇流出异常有关。用来自一名TD患者和一名FHD患者的成纤维细胞进行聚乙二醇（PEG）细胞融合实验，以确定Tangier细胞是否能弥补FHD缺陷。在所有细胞胆固醇流出减少的受试者中，对ABCA1基因的外显子进行测序。
定义为HDL-C水平<第5百分位数的家族性HDL缺乏形式是一组异质性脂蛋白疾病。在7个家系的8名受试者（7/14或50%的受试先证者）中发现细胞胆固醇流出减少，平均比对照减少59%（范围49 - 63%）。在其中4名受试者中，在ABCA1基因位点发现突变。在另外3名受试者中发现流出缺陷，但未在ABCA1基因位点发现关键突变。在其余受试者（7/14）中，未发现流出缺陷。互补研究表明，Tangier细胞不能纠正FHD缺陷，证实FHD和TD代表同一遗传缺陷的不同表现。
家族性低α脂蛋白血症综合征在表型上是异质性的；一种形式与ABCA1基因杂合突变导致的细胞胆固醇流出异常有关，这定义了家族性HDL缺乏，而纯合突变或复合杂合性导致TD。其他形式是原因不明的原发性低α脂蛋白血症，而其余病例与伴有或不伴有载脂蛋白B水平升高的高甘油三酯血症有关。我们得出结论，细胞胆固醇缺陷是家族性HDL缺乏相对常见的原因，并且在这些患者中有一半可鉴定出ABCA1基因突变。
