Alternative titles; symbols
HGNC Approved Gene Symbol: ABCA1
SNOMEDCT: 15346004, 723579009; ICD10CM: E78.6;
Cytogenetic location: 9q31.1 Genomic coordinates (GRCh38): 9:104,781,006-104,928,155 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q31.1 | HDL deficiency, familial, 1 | 604091 | Autosomal dominant | 3 |
| Tangier disease | 205400 | Autosomal recessive | 3 |
ABCA1 functions as a cholesterol efflux pump in the cellular lipid removal pathway.
By a PCR-based approach, Luciani et al. (1994) identified 2 novel mammalian members of the family of ATP-binding cassette (ABC) transporters, designated ABC1 and ABC2 (600047). They belong to a group of traffic ATPases encoded as a single multifunctional protein, such as CFTR (602421) and P-glycoproteins (see 171050). Both ABC1 and ABC2 are large, internally symmetrical molecules that contain complete information for a functional 'channel-like' structure, a feature typical of the mammalian transporters at the plasma membrane. In both ABC1 and ABC2, the 2 halves of the molecules do not share extensive sequence similarity, apart from the nucleotide binding domains. This feature, shared with CFTR and with MRP1 (158343), is in contrast with the high similarity shown by the 2 halves of P-glycoproteins. The finding argues against internal gene duplication as the event giving rise to the symmetric structure and favors the alternative hypothesis of the fusion of 2 independently evolved genes encoding the 2 halves.
Using PCR primers based on the mouse sequence, Langmann et al. (1999) amplified and cloned ABCA1 from differentiated mononuclear phagocytes. The deduced 2,201-amino acid protein has a calculated molecular mass of 220 kD and contains 2 highly conserved ATP-binding cassettes including Walker A and B motifs. The human and mouse ABCA1 proteins share 94% sequence identity. Dot blot analysis of 50 tissues revealed ubiquitous expression of ABCA1 mRNA, with highest expression in placenta, liver, lung, adrenal glands, and all fetal tissues examined, and lowest expression in kidney, pancreas, pituitary, mammary gland, and bone marrow.
Santamarina-Fojo et al. (2000) reported the complete genomic sequence of the ABCA1 gene. The transcription start site was 315 bp upstream of a newly identified initiation methionine codon and encodes an ORF of 6,783 bp. Thus, the ABCA1 protein contains 2,261 amino acids. Analysis of the 1,453 bp 5-prime upstream of the transcriptional start site revealed multiple binding sites for transcription factors with roles in lipid metabolism.
Zhao et al. (2000) also obtained the full-length sequence of ABCA1.
Remaley et al. (1999) reported that the organization of the human ABC1 gene is similar to that of the mouse Abc1 gene and other related ABC genes. They found that the ABC1 gene contains 49 exons, ranging in size from 33 to 249 bp, and is over 70 kb long.
Santamarina-Fojo et al. (2000) found that the ABCA1 gene spans 149 kb and contains 50 exons. They identified 62 repetitive Alu sequences in the 49 introns. Comparative analysis of the mouse and human ABCA1 promoter sequences identified specific regulatory elements that are evolutionarily conserved.
Pullinger et al. (2000) analyzed the promoter region of ABCA1. They identified 7 putative SP1 (189906)-binding sites, 4 sterol regulatory elements (SREs) similar to the SRE of the low density lipoprotein receptor (LDLR; 606945) promoter region, a CpG island, a possible weak TATA box, 2 distal CCAAT sequences, and binding sites for several other transcription factors.
By isotopic in situ hybridization, Luciani et al. (1994) mapped the ABC1 gene to 9q22-q31 and ABC2 to 9q34. In the mouse, the homologs map to chromosomes 4 and 2, respectively, in regions showing homology of synteny to human 9q. Previous results had suggested that the ancestral chromosome split in the mouse lineage at an evolutionary breakpoint situated between hexabrachion (187380) and gelsolin (137350), both of which map to human chromosome 9 and to mouse chromosomes 4 and 2, respectively. Thus, ABC1 and ABC2 probably originated through a duplication event that took place before speciation and predated the splitting of the ancestral chromosome equivalent to human 9q. Their degree of sequence similarity, less impressive than that of the P-glycoprotein isoforms, also argues for a duplication event occurring at an earlier evolutionary stage.
Decottignies and Goffeau (1997) found that the complete sequence of the yeast genome predicts the existence of 29 proteins belonging to the ubiquitous ATP-binding cassette (ABC) superfamily. Using binary comparison, phylogenetic classification, and detection of conserved amino acid residues, they classified the yeast ABC proteins in a total of 6 clusters, including 10 subclusters of distinct predicted topology and presumed distinct function. They pointed out that study of the yeast ABC proteins provided insight into the physiologic function and biochemical mechanisms of their human homologs, such as those involved in cystic fibrosis, adrenoleukodystrophy (300100), Zellweger syndrome (see 214100), multidrug resistance, and the antiviral activity of interferons.
See TAP1 (170260) and TAP2 (170261) for related ABC transporters encoded by genes on 6p21.3.
Since the protein encoded by ABC1 is a key gatekeeper influencing intracellular cholesterol transport, Brooks-Wilson et al. (1999) named it 'cholesterol efflux regulatory protein' (CERP).
Becq et al. (1997) expressed mouse Abc1 in Xenopus oocytes and found that it is a cAMP-dependent and sulfonylurea-sensitive anion transporter.
Lawn et al. (1999) concluded that ABC1 has the properties of a key protein in the cellular lipid removal pathway.
Using primary macrophage cultures, Langmann et al. (1999) induced expression of ABCA1 protein and mRNA with acetylated low density lipoprotein. They reversed the increased expression with cholesterol depletion through the addition of high density lipoprotein.
Young and Fielding (1999) commented on the role of ABC1 in cholesterol efflux.
Using human ABCA1 expressed in the membrane fraction of sf9 insect cells, Szakacs et al. (2001) found specific, Mg(2+)-dependent ATP binding and low basal ATPase activity. Addition of potential lipid substrates or lipid acceptors did not modify the ATPase activity or nucleotide occlusion by ABCA1. Szakacs et al. (2001) speculated that ABCA1 may be a regulatory protein or may require other protein partners for full activation.
Tanaka et al. (2001) found that the electrophoretic mobilities of ABCA1 expressed in transfected HEK293 and COS-7 cells increased when treated with N-glycosidase F, suggesting that ABCA1 is highly glycosylated. They confirmed that ABCA1 binds ATP in the presence of Mg(2+) and showed that ABCA1 expression supports apolipoprotein A-I (APOA1; 107680)-mediated release of cholesterol and choline-phospholipids. They also demonstrated loss of the N-terminal signal peptide in the mature protein. Confocal microscopy showed cell surface immunolocalization in nonpermeabilized cells.
Patients with Tangier disease (205400), caused by mutations in the ABCA1 gene (see MOLECULAR GENETICS), have a defect in cellular cholesterol removal, which results in near zero plasma levels of HDL and in massive tissue deposition of cholesteryl esters. Blocking the expression or activity of ABC1 reduces apolipoprotein-mediated lipid efflux from cultured cells, and increasing expression of ABC1 enhances it (Lawn et al., 1999). ABC1 expression is induced by cholesterol loading and cAMP treatment, and is reduced upon subsequent cholesterol removal by apolipoproteins. The ABC1 protein is incorporated into the plasma membrane in proportion to its level of expression.
In an elegant series of experiments designed to understand the effect of retinoid X receptor (RXR; see 180245) activation on cholesterol balance, Repa et al. (2000) treated animals with the rexinoid LG268. Animals treated with rexinoid exhibited marked changes in cholesterol balance, including inhibition of cholesterol absorption and repressed bile acid synthesis. Studies with receptor-selective agonists revealed that oxysterol receptors (LXRs, see 602423 and 600380) and the bile acid receptor, FXR (603826), are the RXR heterodimeric partners that mediate these effects by regulating expression of the reverse-cholesterol transporter, ABC1, and the rate-limiting enzyme of bile acid synthesis, CYP7A1 (118455), respectively. These RXR heterodimers serve as key regulators in cholesterol homeostasis by governing reverse cholesterol transport from peripheral tissues, bile acid synthesis in liver, and cholesterol absorption in intestine. Activation of RXR/LXR heterodimers inhibits cholesterol absorption by upregulation of ABC1 expression in the small intestine. Activation of RXR/FXR heterodimers represses CYP7A1 expression and bile acid production, leading to a failure to solubilize and absorb cholesterol. Studies have shown that RXR/FXR-mediated repression of CYP7A1 is dominant over RXR/LXR-mediated induction of CYP7A1, which explains why the rexinoid represses rather than activates CYP7A1 (Lu et al., 2000). Activation of the LXR signaling pathway results in the upregulation of ABC1 in peripheral cells, including macrophages, to efflux free cholesterol for transport back to the liver through high density lipoprotein, where it is converted to bile acids by the LXR-mediated increase in CYP7A1 expression. Secretion of biliary cholesterol in the presence of increased bile acid pools normally results in enhanced reabsorption of cholesterol; however, with the increased expression of ABC1 and efflux of cholesterol back into the lumen, there is a reduction in cholesterol absorption and net excretion of cholesterol and bile acid. Rexinoids therefore offer a novel class of agents for treating elevated cholesterol.
Wang et al. (2003) showed that ABCA1 protein degradation is regulated by a PEST sequence (a sequence rich in proline, glutamic acid, serine, and threonine) in ABCA1 and is mediated by calpain protease (see 114170). In a novel form of positive feedback control, the interaction of ABCA1 with apolipoprotein A-I (APOA1; 107680) leads to inhibition of calpain protease degradation and an increase in ABCA1 protein on the cell surface. Wang et al. (2003) suggested that ABCA1 degradation by calpain may represent a novel therapeutic approach to increasing macrophage cholesterol efflux and decreasing atherosclerosis.
Singaraja et al. (2001) developed transgenic mice that expressed human ABCA1. Increased total ABCA1 expression did not alter the pattern of ABCA1 distribution, but resulted in increased cholesterol efflux, elevated HDL cholesterol levels, and increased apoA1 and apoA2 expression. The authors also demonstrated, both in vitro and in vivo, that the ABCA1 gene contains an internal promoter with LXR elements within intron 1. Activation of this functional internal promoter by oxysterols in vivo directly contributed to an increase in human-specific mRNA and protein levels. Singaraja et al. (2001) identified a total of 3 novel ABCA1 transcripts with different transcription initiation sites utilizing sequences in intron 1.
Neufeld et al. (2004) found that late endocytic trafficking was defective in Tangier disease fibroblasts. Late endocytic vesicles accumulated both cholesterol and sphingomyelin and were immobilized in a perinuclear localization. The excess cholesterol in Tangier disease late endocytic vesicles retained massive amounts of NPC1 (607623), which traffics lysosomal cholesterol to other cellular sites. Exogenous apoA1 abrogated the cholesterol-induced retention of NPC1 in wildtype but not Tangier disease late endosomes. Adenovirus-mediated expression of fluorescence-tagged ABCA1 (ABCA1-GFP) in Tangier disease fibroblasts corrected the late endocytic trafficking defects and restored apoA1-mediated cholesterol efflux. ABCA1-GFP expression in wildtype fibroblasts also reduced late endosome-associated NPC1, induced a marked uptake of fluorescent apoA1 into ABCA1-GFP-containing endosomes that shuttled between late endosomes and the cell surface, and enhanced apoA1-mediated cholesterol efflux. Neufeld et al. (2004) concluded that ABCA1 converts pools of late endocytic lipids that retain NPC1 to pools that can associate with endocytosed apoA1 and be released from the cell as nascent HDL.
Nofer et al. (2004) found that ABCA1 is expressed in platelet plasma membranes. Platelets from Tangier patients and Abca1-deficient animals showed impaired responses to collagen and to low concentrations of thrombin, but their responses to ADP remained intact. Tangier platelets were characterized by defective surface exposure of dense body and lysosomal markers, and granules showed an abnormally high pH. Nofer et al. (2004) presented evidence that the impaired response to activation was a consequence of defective dense body function and decreased liberation of agonists during activation. They concluded that ABCA1 deficiency results in a defect in the biogenesis of lysosome-related organelles.
The sterol regulatory element-binding proteins SREBP1 (184756) and SREBP2 (600481) are key transcription regulators of genes involved in cholesterol biosynthesis and uptake. Najafi-Shoushtari et al. (2010) demonstrated that the microRNAs miR33A (612156) and miR33B (613486) embedded within introns of SREBP2 and SREBP1, respectively, target ABCA1 for posttranscriptional repression. Antisense inhibition of miR33 in mouse and human cell lines caused upregulation of ABCA1 expression and increased cholesterol efflux, and injection of mice on a western-type diet with locked nucleic acid-antisense oligonucleotides resulted in elevated plasma HDL. Najafi-Shoushtari et al. (2010) concluded that miR33 acts in concert with the SREBP host genes to control cholesterol homeostasis.
Rayner et al. (2010) demonstrated that miR33, an intronic microRNA located within the SREBF2 gene, a transcriptional regulator of cholesterol synthesis, modulates the expression of genes involved in cellular cholesterol transport. In mouse and human cells, miR33 inhibited the expression of the ATP binding cassette transporter ABCA1, thereby attenuating cholesterol efflux to apolipoprotein A1.
MiR33A and miR33B are intronic miRNAs whose encoding regions are embedded in the sterol response element-binding protein genes SREBF2 and SREBF1, respectively. These miRNAs repress expression of the cholesterol transporter ABCA1, which is a key regulator of HDL biogenesis. Studies in mice suggested that antagonizing miR33a may be an effective strategy for raising plasma HDL levels and providing protection against atherosclerosis; however, extrapolating these findings to humans is complicated by the fact that mice lack miR33b, which is present only in the SREBF1 gene of medium and large mammals. Rayner et al. (2011) showed in African green monkeys that systemic delivery of an anti-miRNA oligonucleotide that targets both miR33a and miR33b increased hepatic expression of ABCA1 and induced a sustained increase in plasma HDL levels over 12 weeks. Notably, miR33 antagonism in this nonhuman primate model also increased the expression of miR33 target genes involved in fatty acid oxidation (CROT, 606090; CPT1A, 600528; HADHB, 143450; and PRKAA1, 602739) and reduced the expression of genes involved in fatty acid synthesis (SREBF1; FASN, 600212; ACLY, 108728; and ACACA, 200350), resulting in a marked suppression of the plasma levels of very low density lipoprotein (VLDL)-associated triglycerides, a finding that had not previously been observed in mice. Rayner et al. (2011) concluded that their results established, in a model that is highly relevant to humans, that pharmacologic inhibition of miR33a and miR33b is a promising therapeutic strategy to raise plasma HDL and lower VLDL triglyceride levels for the treatment of dyslipidemias that increase cardiovascular disease risk.
Aleidi et al. (2018) found that knockdown of HECTD1 (618649) increased ABCA1 protein levels, likely through a posttranslational mechanism, resulting in increased ABCA1-mediated cholesterol efflux to apolipoprotein A-I in human THP1 macrophages, but not in cholesterol-loaded THP1 cells. HECTD1 and ABCA1 associated, as they could be immunoprecipitated together.
Zwarts et al. (2002) identified several SNPs in noncoding regions of ABCA1 that may be important for the appropriate regulation of ABCA1 expression (i.e., in the promoter, intron 1, and the 5-prime untranslated region), and examined the phenotypic effects of these SNPs in 804 Dutch men with proven coronary artery disease. They presented data suggesting that common variation in noncoding regions of ABCA1 may significantly alter the severity of atherosclerosis, without necessarily influencing plasma lipid levels.
Tangier Disease and Familial Hypoalphalipoproteinemia
Brooks-Wilson et al. (1999), Bodzioch et al. (1999), and Rust et al. (1999) identified mutations in the ABC1 gene in patients with Tangier disease (205400), a disorder that is characterized by absence of high density lipoprotein cholesterol from plasma, hepatosplenomegaly, peripheral neuropathy, and frequently premature coronary artery disease. In heterozygotes, HDL cholesterol levels are about one-half those of normal individuals. Impaired cholesterol efflux from macrophages leads to the presence of foam cells throughout the body, which may explain the increased risk of coronary artery disease in some Tangier disease families.
Lawn et al. (1999) detected different mutations in the ABC1 gene in 3 unrelated patients with Tangier disease.
The recessively inherited Tangier disease is sometimes referred to as 'high density lipoprotein deficiency of Tangier type 1.' A more common form of genetic HDL deficiency has been described (familial hypoalphalipoproteinemia, or FHA; 604091) in patients with dominantly inherited low plasma HDL cholesterol, usually below the 5th percentile, but with an absence of clinical manifestations of Tangier disease (Marcil et al., 1995). Marcil et al. (1999) demonstrated that some patients with FHA, or type 2 familial high density lipoprotein deficiency, have reductions in cellular cholesterol efflux that is the same as that observed in Tangier disease. Brooks-Wilson et al. (1999) studied 4 French-Canadian families with FHA and demonstrated mutations in the ABC1 gene, indicating that FHA is allelic to Tangier disease.
Remaley et al. (1999) identified a mutation in the ABC1 gene in the original Tangier disease kindred. Sequence analysis of the ABC1 gene revealed that the proband for Tangier disease was homozygous for a deletion of nucleotides 3283 and 3284 (TC) in exon 22 (600046.0011). The loss of an Mnl1 restriction site, which resulted from the deletion, was used to establish the genotype of the rest of the kindred.
Guo et al. (2002) stated that more than 60 cases of Tangier disease had been reported worldwide. Among Japanese patients, 9 unrelated cases, including 3 in their report, had been described.
Fitzgerald et al. (2002) found that 5 missense mutations were expressed at the plasma membrane but produced little or no apoA1-stimulated cholesterol efflux when transfected into HEK293 cells. All mutants except for one showed a marked decline in interaction between the ABCA1 mutant and apoA1. Fitzgerald et al. (2002) concluded that the deficits shown by these mutations establish their causality in Tangier disease, and that binding of apoA1 by ABCA1 is necessary, but not sufficient, to stimulate cholesterol efflux.
Tanaka et al. (2003) determined that 3 mutations in the first extracellular domain of ABCA1 showed little or no apoA1-mediated HDL assembly when expressed in HEK293 cells. Two of these mutations were associated with impaired glycosylation, retention in the endoplasmic reticulum or the cis-Golgi complex, and failure to localize to the plasma membrane.
Association with Plasma Lipids
Heritable variation underlying complex traits is generally considered to be conferred by common DNA sequence polymorphisms. Cohen et al. (2004) tested whether rare DNA sequence variants collectively contribute to variation in plasma levels of high density lipoprotein cholesterol (HDLC). They sequenced 3 candidate genes that cause mendelian forms of low HDLC levels in individuals from a population-based study. These genes were ABCA1, which is the site of mutations causing Tangier disease, APOA1 (107680), and LCAT (606967), which is the site of mutations causing Norum disease (245900). Nonsynonymous sequence variants were significantly more frequent (16% vs 2%) in individuals with low HDLC (less than fifth percentile) than in those with high HDLC (greater than 95th percentile). Similar findings were obtained in an independent population, and biochemical studies indicated that most sequence variants in the low HDLC group were functionally important. Thus, rare alleles with major phenotypic effects contribute significantly to low plasma HDLC levels in the general population.
Kathiresan et al. (2008) studied SNPs in 9 genes in 5,414 subjects from the cardiovascular cohort of the Malmo Diet and Cancer Study. All 9 SNPs, including rs3890182 (600046.0025) of ABCA1, had previously been associated with elevated LDL or lower HDL. Kathiresan et al. (2008) replicated the associations with each SNP and created a genotype score on the basis of the number of unfavorable alleles. With increasing genotype scores, the level of LDL cholesterol increased, whereas the level of HDL cholesterol decreased. At 10-year follow-up, the genotype score was found to be an independent risk factor for incident cardiovascular disease (myocardial infarction, ischemic stroke, or death from coronary heart disease); the score did not improve risk discrimination but modestly improved clinical risk reclassification for individual subjects beyond standard clinical factors.
Teslovich et al. (2010) performed a genomewide association study for plasma lipids in more than 100,000 individuals of European ancestry and reported 95 significantly associated loci (P = less than 5 x 10(-8)), with 59 showing genomewide significant association with lipid traits for the first time. The newly reported associations included SNPs near known lipid regulators (e.g., CYP7A1, 118455; NPC1L1, 608010; SCARB1, 601040) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contributed not only to normal variation in lipid traits but also to extreme lipid phenotypes and had an impact on lipid traits in 3 non-European populations (East Asians, South Asians, and African Americans). Teslovich et al. (2010) identified several novel loci associated with plasma lipids that are also associated with coronary artery disease. Teslovich et al. (2010) identified rs1883025 in the ABCA1 gene as having an effect on HDL cholesterol concentrations with an effect size of -0.94 mg per deciliter and a P value of 2 x 10(-33).
In a 76-year-old woman carrying a missense mutation in the SCARB1 gene known to be associated with HDL cholesterol levels in the 95th percentile (601040.0003; see HDLCQ6, 610762), but who had an HDLC level at the 15th percentile and a history of early cerebrovascular disease and coronary artery disease, Brunham et al. (2011) identified heterozygosity for a missense mutation (V2091I) in the ABCA1 gene as well. The authors suggested that ABCA1 mutations may be dominant to SCARB1 mutations with respect to HDLC.
Associations Pending Confirmation
In a patient with Scott syndrome (262890), Albrecht et al. (2005) identified a heterozygous missense mutation (arg1925 to gln) in the ABCA1 gene, which was not found in unaffected family members or controls. However, both mutant and wildtype alleles were reduced in mRNA expression, and the authors found no causative mutation for this phenomenon in the ABCA1 gene or its proximal promoter. Albrecht et al. (2005) suggested that a putative second mutation in a trans-acting regulatory gene might be involved in the disorder in this patient.
For a discussion of a possible association between variation in the ABCA1 gene and Alzheimer disease, see 104300.
Orso et al. (2000) demonstrated that mice with a targeted inactivation of Abc1 display morphologic abnormalities and perturbations in their lipoprotein metabolism concordant with Tangier disease. ABC1 is expressed on the plasma membrane and the Golgi complex, mediates apolipoprotein AI (APOA1; 107680)-associated export of cholesterol and phospholipids from the cell, and is regulated by cholesterol flux. Structural and functional abnormalities in caveolar processing and the trans-Golgi secretory pathway of cells lacking functional ABC1 indicated that lipid export processes involving vesicular budding between the Golgi and the plasma membrane were severely disturbed.
To investigate the role of the ABC1 protein in vivo, McNeish et al. (2000) used gene targeting in embryonic stem cells to produce ABC1-deficient mice. Lipid profiles in the knockout mice revealed a reduction of approximately 70% in cholesterol, markedly reduced plasma phospholipids, and an almost complete lack of high density lipoproteins, when compared with wildtype littermates. Dramatic alterations in HDL cholesterol and near absence of apolipoprotein AI were found. Inactivation of the Abc1 gene led to an increase in the absorption of cholesterol in mice fed a chow or a high fat and high cholesterol diet. Histopathologic examination of knockout mice showed a striking accumulation of lipid-laden macrophages and type II pneumocytes in the lungs. The findings demonstrated that the knockout mice had pathophysiologic hallmarks of human Tangier disease and highlighted the capacity of ABC1 transporters to participate in the regulation of dietary cholesterol absorption.
ABCA1 is expressed in Purkinje and cortical pyramidal neurons in the central nervous system (Wellington et al., 2002), as well as in astrocytes and microglia. Hirsch-Reinshagen et al. (2004) found that astrocytes and microglia from Abca1-null mice showed impaired ability to efflux cholesterol to exogenous apolipoprotein E (ApoE; 107741), although residual efflux was present. The mutant cells showed increased intracellular lipid accumulation compared to wildtype cells. In addition, Abca1-null mice showed a 65% decrease in brain levels of ApoE as a consequence of reduced ApoE secretion from mutant glial cells, with the hippocampus and striatum being the most severely affected. Hirsch-Reinshagen et al. (2004) concluded that ABCA1 plays a role in cholesterol transport and ApoE metabolism in the central nervous system.
By analyzing brain tissue, cerebrospinal fluid, plasma, and primary astrocyte cultures from wildtype, Abca1 +/-, and Abca1 -/- mice, Wahrle et al. (2004) determined that deletion of Abca1 markedly affects metabolism of apoE and cholesterol in the central nervous system and in nascent lipoprotein particles secreted by cultured astrocytes.
Brunham et al. (2006) generated intestine-specific Abca1-null mice and found that approximately 30% of the steady-state plasma HDL pool is contributed by intestinal Abca1 in mice. HDL derived from intestinal Abca1 appeared to be secreted directly into the circulation. Analysis of lymph from liver-specific Abca1-null mice with very low plasma HDL showed that HDL in lymph was predominantly derived from the plasma compartment. Brunham et al. (2006) concluded that intestinal ABCA1 plays a critical role in plasma HDL biogenesis in vivo.
Brunham et al. (2007) generated mice with specific inactivation of Abca1 in pancreatic beta cells and observed markedly impaired glucose tolerance and defective insulin secretion but normal insulin sensitivity. Islets isolated from these mice showed altered cholesterol homeostasis and impaired insulin secretion in vivo. The authors found that rosiglitazone, a thiazolidinedione, requires beta-cell Abca1 for its beneficial effects on glucose tolerance. Brunham et al. (2007) concluded that ABCA1 plays a role in beta-cell cholesterol homeostasis and insulin secretion, and suggested that cholesterol accumulation may contribute to beta-cell dysfunction in type 2 diabetes.
Yvan-Charvet et al. (2010) found that deletion of Abca1 and Abcg1 (603076) in mice led to additive defects in macrophage cholesterol efflux and reverse cholesterol transport and accelerated atherosclerosis in a susceptible hypercholesterolemic background. These double-knockout mice also showed marked leukocytosis and infiltration of various organs with macrophage foam cells. Yvan-Charvet et al. (2010) showed that mice deficient in both Abca1 and Abcg1 displayed leukocytosis, a transplantable myeloproliferative disorder, and a dramatic expansion of the stem and progenitor cell population containing lineage-negative Sca1+/Kit+ (164920) (LSK) in the bone marrow. Transplantation of Abca1-null/Abcg1-null bone marrow into apolipoprotein A-1 (107680) transgenic mice with elevated levels of high-density lipoprotein (HDL) suppressed the LSK population, reduced leukocytosis, reversed the myeloproliferative disorder, and accelerated atherosclerosis. Yvan-Charvet et al. (2010) concluded that ABCA1, ABCG1, and HDL inhibit the proliferation of hematopoietic stem and multipotential progenitor cells and connect expansion of these populations with leukocytosis and accelerated atherosclerosis.
In the proband with Tangier disease (TGD; 205400) in a Dutch family, Brooks-Wilson et al. (1999) found compound heterozygosity for mutations in the ABC1 gene. One mutation was a T-to-C transition at nucleotide 4369 in exon 30, predicted to result in a cys1417-to-arg (C1417R) substitution. The other mutation was a G-to-C transversion in the splice donor site of exon 24 (600046.0002), predicted to cause alternative splicing and deletion of a significant part of the transcript.
For discussion of the G-to-C transversion in the splice donor site of exon 24 in the ABCA1 gene that was found in compound heterozygous state in a patient with Tangier disease (TGD; 205400) by Brooks-Wilson et al. (1999), see 600046.0001.
In the proband of a Tangier disease (TGD; 205400) family whose parents were first cousins and in whom haplotype analysis predicted homozygosity, Brooks-Wilson et al. (1999) found homozygosity for an A-to-G transition at nucleotide 1730 in exon 13, resulting in the substitution of arginine for a conserved glutamine at residue 537 (Q537R).
In a French Canadian family with familial high density lipoprotein deficiency (HDLD; 604091), previously reported by Marcil et al. (1995), Brooks-Wilson et al. (1999) found a 3-bp deletion that resulted in loss of nucleotides 2017-2019 and deletion of a leucine at position 633, which is conserved in mouse and C. elegans.
In 1 of 5 families with Tangier disease (TGD; 205400), Bodzioch et al. (1999) found homozygosity for a 1-bp deletion in the ABCA1 gene, removing guanine at nucleotide 1764. This mutation, localized in codon 548, created a frameshift that led to a premature translation stop 26 amino acids downstream of the deletion site. The translation product was predicted to be nonfunctional because it lacked 75% of the amino acid sequence, including all transmembrane regions and both ATP-binding cassettes. Heterozygotes in the family showed decreased HDL cholesterol levels. In this family and 1 other of the 5 reported by Bodzioch et al. (1999), premature coronary artery disease was the major clinical manifestation. In the other 3 families, splenomegaly and hyperplasia of other lymphoid tissues were prominent features.
In a family with Tangier disease (TGD; 205400) reported by Bodzioch et al. (1999), 2 affected individuals were homozygous for a 2744A-G transition that changed asparagine to serine (N875S) in the highly conserved Walker A motif of the amino terminal ATP-binding fold. Splenomegaly and hyperplasia of other lymphoid tissues were prominent features.
In a family with Tangier disease (TGD; 205400), Bodzioch et al. (1999) found compound heterozygosity for 2 missense mutations: a 2750C-T transition, changing alanine to valine (A877V), and a 1709G-C transversion, resulting in a trp530-to-ser (W530S) amino acid substitution (600046.0008).
For discussion of the trp530-to-ser (W530S) mutation in the ABCA1 gene that was found in compound heterozygous state in a family with Tangier disease (TGD; 205400) by Bodzioch et al. (1999), see 600046.0007.
In a German Tangier disease (TGD; 205400) family with premature onset of coronary artery disease, Rust et al. (1999) identified homozygosity for a 1-bp deletion in exon 13 that caused a frameshift and introduction of a stop codon at position 575. The mutation was predicted to result in truncation of the encoded ABC1 protein and deletion of most of the protein sequence, including both ATP-binding cassettes.
In material from a family in Chile in which the clinical diagnosis of Tangier disease (TGD; 205400) was made on the basis of enlarged yellow-orange tonsils and complete absence of HDL from plasma, Rust et al. (1999) found an insertion of a 110-bp DNA fragment structurally related to the Alu sequence family of repetitive sequences and deletion of 14 bp in exon 12 of the ABCA1 gene. This insertion/deletion predicted deletion of 6 amino acids and an in-frame insertion of 38 residues. Neither this mutation nor that described in 600046.0009 allowed the synthesis of the normal ABC1 transporter.
Remaley et al. (1999) demonstrated that in the original Tangier disease (TGD; 205400) family the disorder was caused by homozygosity for a dinucleotide deletion in exon 22 of the ABCA1 gene: 3283-3284delTC. The deletion resulted in a frameshift mutation and a premature stop codon starting at position 3375. The gene product was predicted to encode a nonfunctional protein of 1,084 amino acids, which is approximately half the size of the full-length ABC1 protein.
Lapicka-Bodzioch et al. (2001) developed an assay based on 52 primer sets to amplify all 50 ABCA1 exons and approximately 1 kb of its promoter. The assay allowed for convenient amplification of the gene from genomic DNA and easy mutation analysis through autonomic sequencing. It obviated the need to use mRNA preparations, which were difficult to handle and posed the risk of missing splice junction or promoter mutations. They applied the test to the molecular analysis of a new patient with Tangier disease (TGD; 205400) and found compound heterozygosity for 2 mutations: 2665delC and 4457C-T. These mutations were derived from the father and mother, respectively. The nucleotide substitution caused a ser1446-to-leu substitution (S1446L; 600046.0013). The patient had come to medical attention at the age of 25 years because of splenomegaly and marked reduction of HDL cholesterol as well as ApoA-I and ApoA-II. He had no detectable signs or symptoms of either coronary artery disease or neuropathy.
For discussion of the ser1446-to-leu (S1446L) mutation in the ABCA1 gene that was found in compound heterozygous state in a patient with Tangier disease (TGD; 205400) by Lapicka-Bodzioch et al. (2001), see 600046.0012.
In a Japanese patient with Tangier disease (TGD; 205400), Guo et al. (2002) described homozygosity for a 3199A-G transition in exon 19 of the ABCA1 gene, leading to an asn935-to-ser (N935S) missense mutation. The same mutation had been found in German and Spanish families (Bodzioch et al., 1999; Utech et al., 2001), suggesting that it is a recurrent mutation. The patient was a 69-year-old man who had yellow tonsils. Foamy macrophages were found in the gastric mucosa, and he had not only hepatosplenomegaly but also chronic hepatitis and type 2 diabetes mellitus (125853). He had no cognitive disorder and no coronary artery disease or peripheral neuropathy. In previously reported cases of this mutation, there were no cognitive disorders.
Guo et al. (2002) described a Japanese patient with Tangier disease (TGD; 205400) who was homozygous for a 3198A-C transversion in exon 19 of the ABCA1 gene, resulting in an asn935-to-his missense mutation. This and the asn935-to-ser mutation (N935S; 600046.0014) involved the Walker A motif of the first nucleotide-binding fold. The patient was a 20-year-old man who was diagnosed with obsessive-compulsive disorder. He had mild splenomegaly, but no enlargement of the tonsils and no peripheral neuropathy or coronary artery disease.
Guo et al. (2002) identified a double deletion in the ABCA1 gene in a 57-year-old Japanese male with Tangier disease (TGD; 205400). He had angina pectoris with 90% stenosis of the left anterior descending artery, accompanied by heart failure, yellow tonsils, and hepatosplenomegaly. Foamy macrophages were observed in the tonsils and bone marrow, and stomatocytosis was also noted. The patient's 49-year-old sister had a history of splenectomy and low HDL cholesterol. Guo et al. (2002) used PCR to examine each of the 50 exons of the ABCA1 gene. No PCR products were amplified in exon 12, 13, or 17-31 in this patient. Using long-range PCR, they confirmed double deletions: 1.2 kb from intron 12-14 and 19.9 kb from intron 16-31, which encodes the sixth transmembrane region (a linker region) and the seventh transmembrane region of the putative secondary structure. It was suggested that the double deletion resulted from a single event, as suggested by sequence analysis of the breakpoints. The 3-prime deletion junction had an insertion of 21 bp. The 16 bp within the 21-bp insertion was not found in the original sequence, but was complementary to the proximal sequence of the 5-prime deletion junction. Indeed, the same oriented Alu sequence was found in both intron 14 and intron 31, facilitating the stabilization of the folding of the ABCA1 gene to promote nonhomologous intragenic recombination.
Double deletions in the same gene had previously been reported for dystrophin (300377) by Hoop et al. (1994); in the beta-globin gene (HBB; 141900); in the growth hormone gene (GH1; 139250) by Goossens et al. (1986); and in the GALNS gene (612222), which is mutant in mucopolysaccharidosis type IVA (253000). A simultaneous event of double deletions was proposed for the case of thalassemia patients with changes in the HBB gene because of inversion between the deletions (Jennings et al., 1985; Kulozik et al., 1992).
In a 48-year-old Japanese male, the product of a first-cousin marriage, Ishii et al. (2002) found a clinical variant of Tangier disease (see 205400) manifested by corneal lipidosis and premature coronary artery disease as well as an almost complete absence of HDL cholesterol. Although the patient had no pathognomonic lesions of Tangier disease such as hepatosplenomegaly or peripheral neuropathy, the ABCA1 gene was found to carry homozygosity for an arg1680-to-trp (R1680W) missense mutation.
Ho Hong et al. (2002) identified a patient in whom isolated low high density lipoprotein cholesterol deficiency (HDLD; 604091) was observed at least 5 years before he was diagnosed with cerebral amyloid angiopathy (see 105150). The patient died of complications related to cerebral amyloid angiopathy at the age of 68 years. The patient had a compound heterozygous mutation in the ABCA1 gene. One mutation was a 3295G-T transversion, predicted to result in an asp1099-to-tyr (D1099Y) mutation. The other mutation was a 5966T-C transition, predicted to result in a phe2009-to-ser (F2009S; 600046.0019) mutation. The proband manifested neither cardiovascular disease nor Tangier disease (205400). In the kindred, family members heterozygous for the ABCA1 variant exhibited low levels of HDL cholesterol.
For discussion of the phe2009-to-ser (F2009S) mutation in the ABCA1 gene that was found in compound heterozygous state in a patient with high density lipoprotein deficiency (HDLD; 604091) by Ho Hong et al. (2002), see 600046.0018.
In 2 Japanese sisters with Tangier disease (TGD; 205400), Huang et al. (2001) found compound heterozygosity for 2 mutations in the ABCA1 gene: a 3805G-A transition in exon 27, resulting in an asp1229-to-asn (D1229N) substitution, and a 6181C-T transition in exon 47, resulting in an arg2021-to-trp (R2021W; 600046.0021) substitution.
For discussion of the arg2021-to-trp (R2021W) mutation in the ABCA1 gene that was found in compound heterozygous state in 2 sisters with Tangier disease (TGD; 205400) by Huang et al. (2001), see 600046.0020.
In a Japanese patient with familial high density lipoprotein deficiency (HDLD; 604091), Huang et al. (2001) found homozygosity for a 4-bp deletion (CGCC) at nucleotide 3787, resulting in premature termination by frameshift at codon 1224. The proband, whose mother and all 4 of his children were heterozygous for the mutation, was a 62-year-old man who, at the age of 45 years, presented with bronchial asthma. There was no tonsillar abnormality, lymphadenopathy, hepatosplenomegaly, or xanthomas, and no evidence of neuropathy. Coronary angiography revealed 99% stenosis of the left coronary artery, which required percutaneous transcutaneous coronary angioplasty.
Kolovou et al. (2003) reported a 32-year-old woman with Tangier disease (TGD; 205400), whose parents were second cousins. She had no clinical signs of the disorder except hepatosplenomegaly and no coronary artery disease manifestations. She was found to be homozygous for a 2033C-A transversion in exon 12 of the ABCA1 gene, resulting in conversion of codon 573 from TAC (tyr) to TAA (ter) (Y573X).
This variant, formerly titled CORONARY HEART DISEASE IN FAMILIAL HYPERCHOLESTEROLEMIA, PROTECTION AGAINST, with an included title of HIGH DENSITY LIPOPROTEIN CHOLESTEROL LEVEL QUANTITATIVE TRAIT LOCUS 13, has been reclassified based on a review of the gnomAD database by Hamosh (2019).
In heterozygous familial hypercholesterolemia (FH; 143890) patients, the clinical expression of FH is highly variable in terms of the severity of hypercholesterolemia and the age at onset and severity of coronary heart disease (CHD). Cenarro et al. (2003) hypothesized that ABCA1 may play a key role in the onset of premature CHD in FH. They studied the presence of the arg219-to-lys (R219K) variant in the ABCA1 gene in 374 FH patients with or without premature CHD. The K allele of the R219K variant was significantly more frequent in FH patients without premature CHD than in those with premature CHD, suggesting that the genetic variant may influence the development and progression of atherosclerosis in FH patients. The K allele of the R219K polymorphism seemed to modify CHD risk without important modification of plasma HDL cholesterol levels, and it appeared to be more protective for smokers than nonsmokers.
In a large Swedish population-based study of 1,177 individuals with a first myocardial infarction event and 1,526 healthy controls, Katzov et al. (2006) found an association between the R219K polymorphism and increased serum levels of apolipoprotein B (APOB; 107730) and LDL cholesterol among smokers, but not among nonsmokers.
Hamosh (2019) found that the R219K variant was present in 93,007 of 282,784 alleles, including in 16,973 homozygotes, for an allele frequency of 0.3289 in the gnomAD database (June 19, 2019).
This variant, formerly titled HIGH DENSITY LIPOPROTEIN CHOLESTEROL LEVEL QUANTITATIVE TRAIT LOCUS 13, has been reclassified as a polymorphism based on a review of the gnomAD database by Hamosh (2019).
Kathiresan et al. (2008) replicated the association of rs3890182 (74A-G) in the ABCA1 gene with high density lipoprotein cholesterol levels (HDLCQ13; see 604091) in a study of 5,414 subjects from the cardiovascular cohort of the Malmo Diet and Cancer Study (p = 3.3 x 10(-5)).
Hamosh (2019) found that this variant was present in heterozygous state in 3,553 of 31,336 alleles and in 224 homozygotes, with an allele frequency of 0.1134, in the gnomAD database (June 19, 2019).
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