ArticlesMutations in the ABC 1 gene in familial HDL deficiency with defective cholesterol efflux
Introduction
Coronary-artery disease is the most common cause of death in more developed countries.1 The best lipoprotein discriminator between patients with coronary-artery disease and controls is HDL cholesterol: nearly half of all patients with coronary-artery disease have low concentrations of HDL-cholesterol.23
Genetic factors have a key role in contributing to HDL-cholesterol concentrations. Changes in the genes for apolipoprotein AI-CIII,4 lipoprotein lipase,5 cholesteryl ester transfer protein,6 hepatic lipase,7 and lecithincholesterol acyltransferase,8 all affect HDL-cholesterol concentrations in human beings.
Key steps in the formation of HDL particles are the trafficking of cellular cholesterol to the plasma membrane and its subsequent transfer to nascent HDL particles.9 Some patients with HDL deficiency have a decrease in cellular cholesterol efflux, resulting in cholesterol-depleted HDL particles that are rapidly catabolised; this disorder is known as familial HDL deficiency.1014 In patients with this disorder, no obvious environmental factors are involved, the patients are not diabetic or hypertriglyceridaemic, they do not have known causes of severe HDL deficiency, and they do not have clinical features of Tangier disease.15 In contrast to people with Tangier disease, who have HDL-cholesterol concentrations lower than 0·2 mmol/L, most patients with familial HDL deficiency have HDL-cholesterol concentrations between 0·4 and 0·9 mmol/L.10
We and others have described mutations in the ATP-binding-cassette (ABC 1) transporter gene (which encodes the cholesterol-efflux regulatory protein [CERP]) that causes Tangier disease.1618 This is a rare disorder—it has been diagnosed in about 40 patients worldwide—that is associated with cholesteryl-ester deposition in many tissues.19 We also described one mutation in the same gene in a family with familial HDL deficiency, which is much more common than Tangier disease.16 We could not be certain, however, of the frequency with which mutations in the ABC1 gene underlie HDL deficiency associated with defects in cellular cholesterol efflux.1015
We report mutations in the ABC1 gene in four additional families with familial HDL deficiency associated with defects in cellular cholesterol efflux.
Section snippets
Patients
Patients were selected from the Cardiology Clinic of the Clinical Research Institute of Montréal, Québec, Canada, and the Lipid Research Clinic of the Academic Medical Center, Amsterdam, Netherlands. The main criterion was that the proband had an HDL-cholesterol concentration lower than the fifth centile in normal people, with a plasma concentration of triglycerides less than the 95th centile, and that a first-degree relative had the same lipid abnormality. The patients did not have diabetes or
Biochemical studies
A research nurse contacted family members after they had been contacted by the proband. Blood was withdrawn into edetic-acid-containing tubes for analyses of lipids, lipoprotein cholesterol, apolipoprotein A-I, and triglycerides. Leucocytes were isolated from the buffy coat for DNA extraction.
Lipoprotein measurement was done on fresh plasma as described.20 Concentrations of lipoprotein lipids, cholesterol, and triglycerides were assessed in total plasma, and plasma at a density of less than
Genetic procedures
Four bacterial artificial chromosomes, in total spanning 800 kb, that tested positive by PCR for sequences near both the 5/ and 3/ ends of the ABC1 mRNA were selected for genomic sequencing.16
The human (GenBank accession number AJ012376.1) and mouse (GenBank accession number X75926) ABC1 mRNA sequences were aligned by means of ClaustalW Version 1·7221 and BOXSHADE (http://www.isrec.isb-sib.ch:8080/software/BOXform.html; accessed Oct 7, 1999). Estimated splice-site locations in the human
Results
Three families of French-Canadian descent, and one of Dutch descent, with familial HDL deficiency were enrolled. In each family, fibroblasts from at least one member with low HDL-cholesterol concentrations showed a 50–60% decrease in apolipoprotein A-I-mediated or HDL3- mediated cholesterol efflux compared with fibroblasts from normal controls. Low HDL-cholesterol concentration was inherited as an autosomal dominant trait in all four families. A history of premature coronary-artery disease was
Discussion
HDL deficiency is the most frequent lipoprotein abnormality seen in patients with premature coronary-artery disease. About 4% of such patients have low HDL-cholesterol concentrations as an isolated finding, and another 25% have low HDL-cholesterol concentrations associated with other lipoprotein abnormalities.25
A key step in the formation of the HDL particle is the transport of cholesterol to the plasma membrane where it becomes available for desorption onto HDL particles. The identification of
References (31)
- et al.
Mortality by cause for eight regions of the world: Global Burden of Disease Study
Lancet
(1997) - et al.
Lipoprotein abnormalities associated with a familial deficiency of hepatic lipase
Atherosclerosis
(1982) - et al.
The molecular pathology of lecithin: cholesterol acyltransferase (LCAT) deficiency syndromes
J Lipid Res
(1997) High density lipoprotein metabolism
J Lipid Res
(1984)- et al.
Genomic structure of the canalicular multispecific organic anion-transporter gene (MRP2/cMOAT) and mutations in the ATP binding-cassette region in Dubin-Johnson syndrome
Am J Hum Genet
(1999) - et al.
Amino acid substitutions in the first transmembrane domain (TM1) of P-glycoprotein that alter substrate specificity
FEBS Lett
(1997) - et al.
A prospective study of cholesterol, apolipoproteins, and the risk of myocardial infarction
N Engl J Med
(1991) - et al.
Lipoprotein cholesterol, apolipoproteins A-1 and B, and lipoprotein(a) in men with premature coronary artery disease
J Am Coll Cardiol
(1992) - et al.
A polymorphism in the promoter of the apolipoprotein AI gene associated with difference in apo AI levels: the European Atherosclerosis Research Study
Genet Epidemiol
(1982) - et al.
A lipoprotein lipase mutation (Asn291Ser) is associated with reduced HDL cholesterol levels in premature atherosclerosis
Nat Genet
(1995)
Heterogeneity at the CETP gene locus: influence on plasma CETP concentrations and HDL cholesterol levels
Arterioscler Thromb Vasc Biol
Cellular cholesterol transport and efflux in fibroblasts is abnormal in subjects with familial HDL deficiency
Arterioscler Thromb Vasc Biol
Decreased cholesterol efflux from fibroblasts of a patient without Tangier disease, but with markedly reduced high density lipoprotein cholesterol levels
J Clin Endocrinol Metab
Severe familial HDL deficiency in French Canadian kindred: biochemical and molecular characterization
Arterioscler Thromb Vasc Biol
Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency
Nat Genet
Cited by (324)
A case report of Tangier disease presents with acute sensorimotor polyneuropathy and its treatment approach
2024, Journal of Clinical LipidologyGenomic study of maternal lipid traits in early pregnancy concurs with four known adult lipid loci
2023, Journal of Clinical LipidologyHDL and reverse cholesterol transport in humans and animals: Lessons from pre-clinical models and clinical studies
2022, Biochimica et Biophysica Acta - Molecular and Cell Biology of LipidsHematopoiesis is regulated by cholesterol efflux pathways and lipid rafts: Connections with cardiovascular diseases
2020, Journal of Lipid ResearchCitation Excerpt :A major advancement in the understanding of ABCA1 function was as a consequence of elucidating the basis of Tangier disease, a rare inherited disorder. In humans, mutations in the Abca1 gene result in familial HDL deficiency in which individuals have low HDL levels and apoA-I (55–57). The discovery of the mechanism behind Tangier disease revealed the critical role played by ABCA1 in HDL synthesis via the lipidation of apoA-I (58).
Active polypeptides from Hirudo inhibit endothelial cell inflammation and macrophage foam cell formation by regulating the LOX-1/LXR-α/ABCA1 pathway
2019, Biomedicine and PharmacotherapyCitation Excerpt :ABCA1 is a plasma membrane protein that mediates cholesterol efflux to lipid-poor apolipoproteins and it is critically involved in reverse cholesterol transport [41,42]. The deletion or mutation of ABCA1 leads to a decrease in high-density lipoprotein cholesterol in plasma, increasing the risk of atherosclerosis and coronary artery disease [43]. Mutations in the ABCA1 gene result in Tangier disease and lipid accumulation in macrophages [44].