Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

ABCA Transporters

  • Esther E. Biswas-Fiss
  • Albtool Alturkestani
  • Jazzlyn Jones
  • Joscelyn Korth
  • Stephanie Affet
  • Malissa Ha
  • Subhasis Biswas
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_166


ABCA1:  ABC1;  ATP binding cassette 1;  ATP binding cassette subfamily A member 1;  ATP binding cassette transporter 1;  ATP binding cassette transporter A1;  CERP;  Cholesterol efflux regulatory protein;  HDLDT1;  Membrane-bound;  TGD

ABCA10:  ATP binding cassette subfamily A member 10;  EST698739

ABCA12:  ABC12;  ATP binding cassette 12;  ATP binding cassette subfamily A member 12;  ATP binding cassette transporter 12;  ICR2B;  LI2

ABCA13:  ATP binding cassette transporter A13;  ATP binding cassette subfamily A member 13

ABCA2:  ABC2;  ATP binding cassette 2;  ATP binding cassette subfamily A member 2;  ATP binding cassette transporter 2;  KIAA1062

ABCA3:  ABC transporter 3;  ABC3;  ABC-C transporter;  ABC-C;  ATP binding cassette 3;  ATP binding cassette subfamily A member 3;  ATP binding cassette transporter 3;  EST111653;  LBM180;  SMDP3

ABCA4:  ABC10;  ABCR;  ARMD2;  ATP binding cassette subfamily A member 4;  ATP binding cassette transporter;  ATP binding cassette transporter, retinal-specific;  CORD3;  FFM;  Photoreceptor rim protein;  Retinal-specific ATP-binding cassette transporter;  Retina-specific ABC transporter;  RIM ABC transporter;  RIM protein;  RmP;  RMP;  RP19;  Stargardt disease protein;  STGD;  STGD1

ABCA5:  ABC13;  ATP binding cassette A5;  ATP binding cassette subfamily A member 5;  EST90625;  KIAA1888

ABCA6:  ABC transporter ABCA6;  ATP binding cassette A6;  ATP binding cassette subfamily A member 6;  EST155051

ABCA7:  ABCA-SSN;  ABCX;  ATP binding cassette subfamily A member 7;  Autoantigen SS-N;  Macrophage ABC transporter

ABCA8:  ATP binding cassette subfamily A member 8;  KIAA0822

ABCA9:  ATP binding cassette A9;  ATP binding cassette subfamily A member 9;  EST640918

Historical Background

ATP binding cassette (ABC) transporters represent members of a transmembrane protein superfamily that bind and hydrolyze ATP to mediate the transport of a wide array of substrates across extra- and intracellular membranes in organisms ranging from prokaryotes to man. In the human genome, 49 ABC genes have been identified to date, which have been additionally divided into eight subfamilies ABCA through ABCH (Albrecht and Viturro 2007; Dean et al. 2001; Higgins 2001; Kaminski et al. 2006; Theodoulou and Kerr 2015; Vasiliou et al. 2009; Zhang et al. 2016). Those belonging to subfamilies E and F lack transmembrane domains and are thus thought to have functions other than transport. This review will focus on the ABCA subfamily consisting of 12 members uniformly present in humans and most vertebrate species; ABCA1-ABCA13, with the exception of ABCA11 which appears to be a pseudo gene. Interestingly, genomic studies have recently identified these 12 members in various species of plants (Lane et al. 2016). Four additional members of the ABCA family, ABCA14-17, have been identified in rodents; however, as yet no orthologs have been described in humans, and as a result will not be discussed here. Within the ABCA subfamily, the transporters ABCA5, ABCA6, ABCA8, ABCA9, and ABCA10 share significant sequence homology and form a gene cluster locus on chromosome 17q (Table 1); these five transporters are sometimes referred to as the “ABCA6-like transporters.” The importance of ABCA proteins are underscored by the fact that loss of function mutations in their genes are linked to a number of inherited diseases, such as Tangier disease (ABCA1), Stargardt macular dystrophy (ABCA4), and Harlequin ichthyosis (ABCA12). ABCA gene expression patterns have also been linked to cancer outcomes and drug resistance (Cui et al. 2015; Hedditch et al. 2014).
ABCA Transporters, Table 1

ABCA subfamilies and associated characteristics



Length (aa)


Functional significance

Associated diseases





Cholesterol homeostasis

Tangier disease, Alzheimer’s disease, atherosclerosis





Neuronal associated lipid transport; drug resistance in cancer

Alzheimer’s disease




Lung (alveolar type II cells), Human lens capsule, Choroid-retinal pigment epithelium, retinal pigment epithelial cells

Pulmonary surfactant secretion; drug resistance in cancer

Fatal surfactant deficiency, interstitial lung disease, cataract-microcornea syndrome




Rod and cone photoreceptors, brain

Transports retinal

Inherited macular degeneration (STGD, CRD, FFM, arRP)




Skeletal muscle, kidney, liver, hair follicles

Intracellular trafficking

Recessive congenital hypertrichosis




Ubiquitously liver, lung, heart, brain, and ovaries

Macrophage lipid transport

Follicular lymphoma, ovarian cancer




Spleen, thymus, and bone marrow, highly on microglia of the brain

Lipid transport

Alzheimer’s disease




Heart, liver, and muscle

ATPase-dependent drug transport function, myelin production





Heart (CDD) but diverse throughout the body

Macrophage lipid homeostasis

Ovarian cancer




Muscle, heart (CDD)

Lipid transport





Keratinocytes placenta, skin, testis, and fetal brain

Lipid trafficking

Harlequin ichthyosis, lamellar ichthyosis type 2




Trachea, testis, brain, bone marrow

Cellular function unknown; marker for chemotherapy response


Bipolar disorder?

Underlying themes in ABCA subfamily member’s association with disease are defects in transport of specific lipid-based substances. This report will discuss ABCA subfamily protein structure and membrane topology, cellular function and disease associations, the intersection of ABCA transporters with cell signaling pathways, and lastly future directions of ABCA research.

Common Structural Features of ABCA Subfamily Members

The prototypical mammalian ABCA transporter consists of two transmembrane domains (TMDs) and two nucleotide-binding domains (NBDs) encoded by a single polypeptide chain (Fig. 1). The nucleotide binding domains (NBDs) are responsible for hydrolyzing ATP to provide for energy to drive the conformational change required to transport substrates across the extra- or intracellular membranes (Albrecht and Viturro 2007; Kaminski et al. 2006). The nucleotide-binding domains are the most highly conserved regions among members of the ABC transporter family. Each nucleotide-binding domain contains Walker A (GXXGXGK(T/S)) and Walker B ([RK]-x(4)-G-x(4)-LhhhhD, h = hydrophobic) motifs, and are followed by a conserved 80-residue ABCA signature sequence (-S/T-S/T-h-D/E-D/E). The TMDs are believed to participate in substrate translocation and thus share little homology with other members of the subfamily. Additional conserved sequence motifs have been identified, including an N-terminal xLxxKN and C-terminal VFVNFA (ABCA1, ABCA2, and ABCA4); these motifs are believed to be important for cellular trafficking and efflux activity, respectively (Beers et al. 2011; Fitzgerald et al. 2004; Stenirri et al. 2006; Zhong et al. 2009).
ABCA Transporters, Fig. 1

Predicted structural organization of ABCA proteins and their important functional domains. Pictorial representation showing the cytoplasmic nucleotide binding (NBD), extracellular/extra-lumenal (ECD), and transmembrane domains (TM) of a typical ABCA protein

Structural topology varies significantly between the eight subclasses of ABC transporters. In the ABCA subfamily each half transporter contains a transmembrane domain comprised of six membrane spanning helices, followed by a soluble domain containing a NBD. In addition, each ABCA half transporter possesses a large extracellular loop, which is a characteristic unique to this subfamily (Fig. 1) (Bungert et al. 2001; Kaminski et al. 2006; Peelman et al. 2003). The ABCA subfamily has some of the largest ABC proteins identified to date, one of which (ABCA13) is over 5000 amino acids long and greater than 570 kDa in predicted molecular mass (Albrecht and Viturro 2007; Kaminski et al. 2006) (Table 1).

Unifying Themes Among ABCA Subfamilies

The research gathered to date suggests that this ABCA subgroup of 12 structurally related “full size” transporters mediates the transport of a variety of physiologic lipid compounds in an ATP hydrolysis dependent manner. A few subfamilies have particular similarities between them such as ABCA12 and ABCA3 which are exclusively localized in a secretory intracellular lipid storage compartment such as lamellar granules in keratinocytes and as well as in lamellar bodies in pneumocytes. Besides cellular location similarities several subfamilies have close homology with one another such as ABCA9 who displays the highest amino acid sequence identity with ABCA8 (78%), ABCA6 (68%), ABCA10 (71%), and ABCA5 (53%) (Albrecht and Viturro 2007; Kaminski et al. 2006; Ordovas 2000) Fig. 2. The detailed mechanism of transport has yet to be determined for any of the mammalian ABCA transporters, so it is not yet known if this will be a unifying feature of this group. Collectively this group is associated with a wide range of heritable disorders, display distinct tissue distribution and regulation of gene expression, and underscore the critical importance of lipid homeostasis in human health and disease.
ABCA Transporters, Fig. 2

Phylogenetic tree of human ABCA-subfamily transporter genes. Full length amino acid sequences were aligned using CLUSTAL (http://bips.u-strasbg.fr/fr/Documentation/ClustalX/), and phylogenetic analysis was performed utilizing the PHYLIP software (http://evolution.genetics.washington.edu/phylip.html). Bootstrap values (%) out of 100 iterations are indicated at each branch point

Figure 1 depicts a pictorial representation showing the cytoplasmic nucleotide binding (NBD), extracellular (ECD), and transmembrane domains (TM) of a typical ABCA protein.


Perhaps the most well-characterized ABCA transporter, the ABCA1 protein is expressed in a large number of human tissues with the highest levels present in the placenta, liver, lung, adrenal glands, and fetal tissues. The ABCA gene is localized to chromosome 9q31 and spans 50 exons. The 149 kb ORF encodes a 2261 aa polypeptide with a predicted molecular mass of 254 kDa (Table 1). ABCA1 has been identified to be a major regulator of HDL metabolism, and mutations in this gene have been shown to be responsible for Tangier’ disease (Ordovas 2000). ABCA1 is believed to orchestrate cellular phospholipid and cholesterol active transport. It is required for optimal lipidiation of ApoA-1 in nascent HDL biogenesis and promotes the unidirectional efflux of cholesterol and phospholipids from the cell (Fitzgerald et al. 2010). To date over 50 disease-associated mutations have been identified in the ABCA1 gene (Fasano et al. 2005). Individuals heterozygous for ABCA1 mutations are at increased risk for familial high density lipoprotein deficiency (FHD) and atherosclerotic cardiovascular disease (ACVD) and may play a role in age-related macular degeneration (Yu et al. 2011). Molecular diagnostic testing is increasingly becoming available to aid in the diagnosis of ABCA1-related diseases (Akao et al. 2014). Recent studies have continued to expand the role of ABCA1 in human health and disease. ABCA1 appears to play a role in cognitive impairment brain-related pathologies; loss of function ABCA1 variants are associated with increased risk Alzheimer’s disease, and increased brain amyloid levels have been observed in (ABCA1−/−) mice (Nordestgaard et al. 2015; Yassine et al. 2016). The use of ABCA1 agonists shows potential for their ability to counteract A-beta42 accumulation in mice (Boehm-Cagan et al. 2016). ABCA1 may also play a role in diabetes, as it appears to be involved in regulating β-cell cholesterol homeostasis and insulin secretion (Rickels et al. 2015).

In executing its cellular function, ABCA1 interacts with ApoA-I protein, oligomerizing to form a homotetramer which leads to the development of a high affinity lipid binding site. ApoA-I appears to interact with ABCA1 through its extracellular domains. Interaction with ApoA-I activates the phosphatidylcholine pathway by upregulating phosphatidylcholine synthase (Iatan et al. 2011). Interferon γ decreases ABCA1 expression levels in a JAK/STAT regulated manner (Fitzgerald et al. 2010). Recent studies suggest that ABCA1-related ACVD could be treated using peroxisome proliferator-activated receptors (PPARs) and LSR agonists which have been shown to influence ABCA1 gene expression (Wakino and Itoh 2010). Recently, ABCA1 has been shown to play a role in sphingosine-1-phosphate (S1P) cell signaling. Inhibitor and siRNA experiments demonstrate that ABCA1 and SR-BI are required for S1P release and ERK1/2 phosphorylation induced by apoA-I (Boehm-Cagan et al. 2016).


ABCA2 is highly expressed in the cells of the nervous (CNS), ovary, and hematopoietic systems. Functionally it is associated with lipid transport and drug resistance in cancer cells, including tumor stem cells. Cellular immunolocalization revealed colocalization of ABCA2 with late endolysomes and trans-Golgi organelles where it appears to function in cholesterol homeostasis and LDL metabolism (Mack et al. 2006). The gene is localized to chromosome 9q34.3 spanning 48 exons. The 149 kb ORF encodes a 2436 aa polypeptide with a predicted molecular mass of 270 kDa. Alternative splicing of the first exon to the second results in two variants, 1A and 1B.

Studies have indicated a relationship between ABCA2 and both early onset and late onset/sporadic Alzheimer’s disease (AD). In vitro studies showed that ABCA2 is highly expressed in human neuroblastoma cells and colocalizes with beta-amyloid; overexpression of ABCA2 increased amyloid precursor protein (APP) protein levels. Davis found that overexpression of ABCA2 modulates sphingolipid levels which in turn regulate transcription of the APP gene (Davis 2015). Furthermore, downregulation of ABCA2 reduces amyloid-β production by altering Nicastrin, part of the gamma secretase protein complex, maturation and intracellular localization (Michaki et al. 2012). A single nucleotide polymorphism in human ABCA2 has been found to be associated with early development of this disease (Mace et al. 2005). ABCA2 is a cholesterol responsive gene along with ABCA1 and ABCA7. ABCA2 expression levels correlate with the esterification of plasma membrane derived cholesterol through modulation of sphingolipid metabolism (Davis 2014).

ABCA2 is involved in drug efflux and plays a role in multidrug resistance in cancers, including lung, childhood acute lymphoblastic leukemia, and estrogen sensitive cancers (Gao et al. 2015; Mack et al. 2012; Rahgozar et al. 2014). Thus, evaluation of ABCA2, along with several other ABC transporter gene expression profiles may aid in the design of more efficient treatment strategies. MicroRNA-mediated downregulation of the ABCA2 gene product has been observed in untreated colon cancer suggesting a possible therapeutic manipulation of gene expression in the future.


The ABCA3 protein is highly expressed in the lung and has been localized primarily to the outer, or limiting, membrane of the lamellar body. Studies have revealed that in the lung ABCA3 is expressed exclusively at the limiting membrane of the lamellar bodies in the type II cells in human lung alveolar structures. The ABCA3 gene is localized to chromosome 16p13.3 spanning 33 exons. The ORF encodes a 1704 aa polypeptide with a molecular mass of 191 kDa (Table 1). Consistent with glucocorticoid responsive regulation of gene expression, determined expression of ABCA3 increased more than 30-fold following stimulation of fetal lung explants with dexamethasone, cAMP, and isobutylmethylxanthine (Kaminski et al. 2006; Takahashi et al. 2005; van der Deen et al. 2005).

ABCA3 has been shown to play an important role in the formation of pulmonary surfactant which lowers the surface tension at the air–liquid interface thus preventing the collapse of the alveoli. A wide range of mutations (>150) within ABCA3 have been linked to fatal respiratory distress syndrome in the neonatal period and with interstitial lung disease in older infants, children, and adults (Wert et al. 2009). ABCA3 genetic testing is now available and identification of variants is increasingly common in the diagnosis of pediatric respiratory syndromes (Peca et al. 2015; Turcu et al. 2013; Xie et al. 2016a). ABCA3 appears to function to import surfactant phospholipids, such as phosphatidylcholine (PC) and phosphatidylglycerol (PG), from the cytosol into the lamellar body and is thought, therefore, to be important for lamellar body biogenesis. STAT3, activated by IL6, regulates ABCA3 expression and influences lamellar body formation in alveolar type II cells (Matsuzaki et al. 2008). Recently, variants in ABCA3 were associated with dominant cataract-microcornea syndrome, a congenital form of early childhood blindness 1. Chen et al. identified ABCA3 as a novel pathogenic causative gene for CCMC, as evidenced by several different heterozygous missense mutations identified in two autosomal dominant CCMC families and sporadic patients. The study aimed to identify disease-associated genes in Chinese patients with CCMC, in addition to the known genes encoding for crystallins, by using the whole exome sequencing technique. It is predicted that the ABCA3 glycoprotein may utilize the energy derived from the hydrolysis of ATP for substrate transport involved in eye development. As the role of the ABCA3 gene in eye development remains unknown, future investigation of the ABCA3 gene is needed to determine its function in eye development and in turn its relationship with dominant CCMC pathogenesis. Increased mRNA expression levels of ABCA3 were identified as a risk factor for multidrug resistence in the treatment of childhood acute lymphoblastic leukemia (ALL) (Rahgozar et al. 2014). Despite these disease associations, the cellular and physiological functions of ABCA3 remain unknown. The C. elegans protein ced7 is homologous to human ABCA3. Ced-7 functions in the engulfment of cell corpses during programmed cell death although it is not known if mammalian ABCA3 also performs a similar function.


ABCA4 (previously referred to as ABCR or the rim protein) is a retina-specific member of the ABCA subfamily. It was the first ABCA transporter to be causatively linked to genetic disease (Allikmets et al. 1997). The ABCA4 gene spans nearly 150 kb and contains at least 50 exons (Table 1). It encodes a 2273 amino acid protein which is localized in the retina along the rims of rod and cone photoreceptor outer segment disk membranes. ABCA4 may act as an ATP-dependent flippase that translocates N-retinylidene-phosphatidylethanolamine (−PE) from the lumen to the cytoplasmic side of the disk membrane (Pollock and Callaghan 2011; Tsybovsky et al. 2010). This action is required for the continued recycling of all–trans retinal released from photo-bleached rhodopsin as part of the visual transduction cycle. Studies conducted with ABCA4 (−/−) mice support the hypothesis that lack of ABCA4 transport activity may lead to the accumulation of toxic all–trans retinal derivatives (lipofuscin) in the rod and cone cells, leading to apoptosis of the supporting retinal pigment epithelium and, eventually, the photoreceptors themselves (Mata et al. 2001). This view was in agreement with the observations that ABCA4 binds the retinoid N-retinylidene-PE with high affinity (Molday et al. 2006). Studies have shown the ECD2 domain of ABCA4 specifically interacts with all–trans retinal (Biswas-Fiss et al. 2010). More recently, biochemical and whole mouse studies have suggested that ABCA4 is also important for 11-cis retinal import, uniquely positioning ABCA4 as in importer, as well as exporter of retinoids (Biswas-Fiss et al. 2012; Boyer et al. 2012).

To date >800 sequence variations in the ABCA4 gene have been identified which are linked to four macular degenerative diseases including Stargardt disease (STGD), cone-rod dystrophy (CRD), autosomal retinitis pigmentosa type 19 (RP19), and age-related macular degeneration (AMD) (Pollock and Callaghan 2011; Tsybovsky et al. 2010). Genotyping of patients is now possible and the future hold promise for some in the form of gene therapy (Hafler 2016). With the advent of next-generation DNA sequencing technologies, a challenge today is to correlate the numerous ABCA4 variants with the broad range of clinical phenotypes and to understand this translates to ABCA4 protein dysfunction at a molecular level. Bioinformatic assessment of variants of unknown significance may aid in this endeavor. Likewise, development of a transport functional assay would be a major step towards this goal.

ABCA6-Like Transporters

Five closely related members of the human ABCA subfamily form a compact cluster on chromosome 17q24.2-3, comprising the genes for ABCA5, 10, 6, 9, 8 (in that order) (Table 1). The common chromosomal location of these ABCA6-like transporters and their overall high peptide sequence homology strongly supports the hypothesis that these transporters evolved from a common ancestral gene (Annilo et al. 2003; Dean et al. 2001). The exact cellular function of ABCA6-like transporters remains unclear although defined roles are beginning to emerge. Early studies pointed to a collective contribution of these gene products, for example, studies suggest that ABCA6, ABCA9, and ABCA10 may play a role in the connective tissue disorder pseudoxanthoma elasticum (PXE) (Schulz et al. 2006). In other instances, the ABCA6-like transporters play distinct functions as described below.

Immunohistochemical studies revealed that ABCA5 is highly expressed in cardiomyocytes of the heart, oligodendrocytes and astrocytes of the brain, alveolar type II cells of the lung, and Leydig cells of the testis. Mounting evidence seems to suggest that ABCA5 is involved in neurodegenerative disease, cancer as well as a rare form of congenital generalized hypertrichosis terminalis (DeStefano et al. 2014). ABCA5 was found to be significantly elevated in Parkinson’s disease brains compared to age- and gender-matched controls (Kim and Halliday 2012). In a cell culture model, ABCA5 levels are increased in the presence of sphingomyelin. ABCA5 may also be important in the pathology of Alzheimer’s disease as suggested by gene expression patterns in mouse brain, and its apparent correlation with Aβ42 peptide levels (Fu et al. 2015). ABCA5 has emerged as a biomarker for osteosarcoma, prostate, ovarian, and colon cancer (Hedditch et al. 2014; Karatas et al. 2016; Ohtsuki et al. 2007; Saini et al. 2012).

Genome-wide association studies and proteomic analysis have added to the knowledge base of ABCA6. The finding that ABCA6 variants identified in Dutch populations adversely affect cholesterol levels confirms the notion that ABCA6 is important of lipid homeostasis (van Leeuwen et al. 2015). The finding that the genes for ABCA6, 9, and 10 are regulated by cholesterol in human macrophages suggests their potential involvement in lipid transport processes in these cells (Fitzgerald et al. 2010; Kaminski et al. 2006; Takahashi et al. 2005). Survival rates in epithelial ovarian cancer and follicular lymphoma appear to point to a role of the “ABC6 like” transporter in multidrug resistance. In a small-scale study, SNPs identified in ABCA10 and ABCA6 variants were shown to influence the survival rate in follicular lymphoma (Baecklund et al. 2014). Gai and coworkers identified two functional FoxO-responsive elements in the ABCA6 promoter, implicating ABCA6 as a downstream effector of the Foxhead signaling pathway. In vascular endothelial cells, ABCA6 mRNA transcription was stimulated by cholesterol and inhibited by Insulin-like growth factor 1 (Gai et al. 2013).

Despite limited understanding on the detailed mechanism of action of ABCA8, prognostic assays for several cancers have been developed using this transporter as a diagnostic indicator. A promising five gene RT-PCR assay, which includes ABCA8, has been developed to accurately allow for classification of breast fibro-epithelial lesions. Preoperative distinction between fibroadenomas and phyllodes tumors is pivotal to clinical management (Tan et al. 2016). Analysis of ABCA8 expression levels has also proved valuable in predicting drug resistant cases of ovarian and pediatric medullary cancers (Hedditch et al. 2014; Ingram et al. 2013; Januchowski et al. 2013; Januchowski et al. 2014; Liu et al. 2015). Emerging evidence suggests ABCA8 also appears to play a role in brain-lipid homeostasis. Studies have demonstrated ABCA8’s tissue specific gene expression in the choroid plexus of mouse and human brain. Subsequently it has been shown that ABCA8 specifically regulates sphingomyelin production in oligodendrocytes. Thus, given the requirement for sphingomyelin in the formation of lipid rafts to transport myelin constituents needed for myelination, it would appear ABCA8 is involved in myelination. Analysis of patients with multiple system atrophy (MSA) has shown an eight-fold upregulation of ABCA8, which in turn may account for dysregulation of lipid transport and the accompanying pathology (Bleasel et al. 2013; Kim et al. 2013; Wong et al. 2014).

ABCA10 has emerged as a novel putative marker for epithelial ovarian cancer, where along with ABCA9 and ABCC9, its expression levels were correlated with progression free survival rates. Further studies are required to validate this finding and to elucidate its role in carcinogenesis or chemoresistance (Elsnerova et al. 2016).

Much remains to be understood about this subgroup of ABCA transporters, including their disease associations, transported ligands, and the physiological significance of their clustering at the 17q24 locus.


The ABCA7 transporter gene was initially cloned from human macrophages in which it is subject to regulation by cholesterol influx and efflux via the sterol regulatory binding element 2 (Tanaka et al. 2011). The ABCA7 gene contains 46 exons, spans nearly 32 kb and is localized to chromosome 19p13.3. The ORF encodes a 2146 amino acid protein with a predicted molecular weight of 235 kDa. Its expression levels are regulated in a manner opposite that of ABCA1 protein, which is upregulated in the presence of sterols. ABCA7 is highly expressed in myelo-lymphatic tissues with highest expression in peripheral leukocytes, thymus, spleen, and bone marrow, but it was also found in platelets and keratinocytes (Fitzgerald et al. 2010; Kaminski et al. 2006; Takahashi et al. 2005). ABCA7 shows the greatest homology with ABCA1 (55%) and ABCA4 (49%) transporters. ABCA7 has been implicated in the regulation of ceramide and phospholipid export from the cell since it is predominantly localized intracellularly (Kim et al. 2008; Takahashi et al. 2005; Wang et al. 2003). The precise physiological role of ABCA7 remains uncertain. Tanaka and coworkers observed identity between the ECD1 domain (residues 195 and 352) of ABCA7 and a Sjogren syndrome autoantigen (Tanaka et al. 2003). They determined that ABCA7 encodes the autoantigen SS-N and plasma cells infiltrating salivary glands of patients with Sjögren’s syndrome were immunoreactive against a monoclonal antibody derived from the ABCA7 ECD1.

ABCA7 mediates the formation of HDL when exogenously transfected and expressed; however, no endogenous effect of ABCA7 in HDL formation has been found. Recently, ABCA7 has been linked to phagocytosis regulated by sterol regulatory element binding protein 2. Coupled with the observation that HDL apolipoproteins stabilize ABCA7 against calpain mediated degradation, ABCA7 may represent a link between sterol homeostasis and the host-defense response infection, inflammation, and apoptosis (Tanaka et al. 2003). Further research is required to delineate the specific substrate(s) of ABCA7 and its precise physiological function in these processes.

Most recently, genome-wide association studies strongly support a correlation between the variations in levels of ABCA7 gene expression or the existence of ABCA7 genetic variants with the development of Alzheimer’s disease (Cuyvers et al. 2015; Del-Aguila et al. 2015; Nuytemans et al. 2016; Steinberg et al. 2015; Van den Bossche et al. 2016; Zhao et al. 2015). Disease associated variants were identified in African Americans with late onset Alzheimer’s disease (LOAD), and subsequently it was found that disease associated variants are found in individuals with European and Caucasian ancestry as well (Barber 2012; Carrasquillo et al. 2011; Chung et al. 2013b; Cukier et al. 2016; Cuyvers et al. 2015; Del-Aguila et al. 2015; Hohman et al. 2016; Logue et al. 2011; Shi et al. 2012). ABCA7 variants were not associated with increased risk of LOAD in Chinese or Korean populations examined (Chung et al. 2013a; Liao et al. 2014; Tan et al. 2013). Much remains to be understood regarding the role of ABCA7 variants and its relation to Alzhemier’s disease, and emerging evidence suggest that decreased expression, or impaired function, of ABCA7 may contribute to AD pathology (Bamji-Mirza et al. 2016; Fu et al. 2016; Yu et al. 2015). Further research is necessary to correlate the cellular and biochemical basis of ABCA7 missense variants and their role in the development and progression of Alzheimer’s disease.


ABCA11 is considered a pseudogene as no functional “ABCA11” gene sequence has been found in Homo sapiens (Kaminski et al. 2006).


ABCA12 is a keratinocyte transmembrane lipid transporter protein associated with the transport of lipids in lamellar granules (LG) to the apical surface of granular layer keratinocytes. ABCA12 localizes throughout the entire Golgi apparatus to LGs at the cell periphery, mainly in the granular layer keratinocytes. ABCA12 was first identified in human placenta besides being highly expressed in the skin, testis, and fetal brain (Annilo et al. 2002; Kaminski et al. 2006; Wenzel et al. 2007). The gene is composed of 53 exons and maps to chromosome 2q35. ABCA12 mutations are known to underlie the three main types of autosomal recessive congenital ichthyoses: harlequin ichthyosis, lamellar ichthyosis, and congenital ichthyosiform erythroderma (Albrecht and Viturro 2007). Fifty-two mutations have been identified to date. Studies have shown that the nature and severity of mutations in the ABCA12 gene accounts for the resulting clinical phenotype: harlequin ichthyosis (HI) is a severe form of congenital ichthyosis, while the second phenotype is a milder form manifesting as lamellar ichthyosis type 2 (Kaminski et al. 2006). HI is the most severe of these diseases and is typically fatal in the first few days of life. The availability of genetic testing for ABCA12 has enabled for more accurate diagnosis and management of disease (Koochek et al. 2014; Peca et al. 2015; Xie et al. 2016b). Ceramide was reported to upregulate ABCA12 expression via peroxisome proliferator-activated receptor (PPAR) delta-mediated signaling pathway, providing a substrate-driven, feed-forward mechanism for regulation of this key lipid transporter. The recent development of a mouse model of ABCA12-mediated ichthyosis will no doubt aid in understanding the molecular basis of these diseases (Zhang et al. 2016).


ABCA13 represents the largest ABC transporter comprising 5058 amino acids (Prades et al. 2002). In normal tissues the highest mRNA expression of the ABCA13 full length mRNA was found in human trachea, testis, and bone marrow. Prades et al. (2002) determined that the ABCA13 gene contains 62 exons and spans more than 450 kb. Exons 17 and 18 are large, containing 4779 and 1827 bp, respectively. Research has found that ABCA13 shares a common genomic region on chromosome 7p12.3 with the locus linked to the T-cell tumor invasion and metastasis, INM7 (Prades et al. 2002). ABCA13, being linked to INM7 while also displaying high expression levels in leukemic cells, may play a possible role in hemato-oncological pathologies (Kaminski et al. 2006; Ma et al. 2013). Elevated expression levels of ABCA13 are also correlated with poor outcomes of gastric, ovarian, and colorectal cancers (Arai et al. 2014; Araujo et al. 2016; Nymoen et al. 2015). Perhaps more controversial are human genetic data suggesting variants in the ABCA13 locus are associated with schizophrenia, bipolar disorder, and depression (Knight et al. 2009; Ma et al. 2013; Pickard et al. 2012). As ABCA13 variants have been shown to correlate with psychiatric disorders in some, but not all, ethnic populations, their significance remains uncertain. Despite these insights into the physiological role of ABCA13, further studies are required to determine the exact functional role and physiological substrate of this transporter.



The ABCA subfamily form an intriguing group of transporters whose function relates to lipid homeostasis. Although in several instances, such as with the ABCA6-like subgroup, the exact cellular function and mechanism of action remain unknown, their important physiological role is underscored by the often severe diseases that result from mutations in their genes. Prospects for future research relate back to the degree in which each transporter is understood. For relatively well-characterized transporters such as ABCA1 and ABCA4, a significant amount is known about the prospective ligand and a well-established link between a given monogenic disorder and mutations in the transporter encoding gene exists. Genetic testing for ABCA1, ABCA4, ABCA3,ABCA7, and ABCA12 disease associated variants is available in laboratories in the United States and abroad. For these transporters current and future research aimed at understanding the genotype phenotype (biochemical as well as clinical) correlation is important, so that more accurate prognoses and specific therapies may be implemented. Ultimately, the development of transport assays which can analyze the actual transport event itself, for both mutant and wild type proteins, will need to be developed in order to determine the precise effect of a given mutation on transporter function. In the case of less well understood transporters, such as the ABCA6-like subgroup, fundamental research is required to determine the identity of the transport ligand and how this relates to human health and disease. Finally, defining the role of protein-protein interactions in ABCA proteins is necessary in order to determine the synergistic relationships between the other members of the ABCA and/or ABC protein family as well as to define a given ABCA proteome. Perhaps, the recent identification of ABCA transporters in plants may provide us with additional model systems. Undoubtedly, the roadmap of ABCA disease-associated variants provides scientists and clinicians with a wealth of clues to uncover the secrets of this important class of ABC transporters.


  1. Akao H, Polisecki E, Schaefer EJ, Trompet S, Robertson M, Ford I, et al. ABCA1 gene variation and heart disease risk reduction in the elderly during pravastatin treatment. Atherosclerosis. 2014;235(1):176–81. doi:10.1016/j.atherosclerosis.2014.04.030.PubMedCentralCrossRefPubMedGoogle Scholar
  2. Albrecht C, Viturro E. The ABCA subfamily – gene and protein structures, functions and associated hereditary diseases. Pflugers Arch. 2007;453(5):581–9. doi:10.1007/s00424-006-0047-8.CrossRefPubMedGoogle Scholar
  3. Allikmets R, Shroyer NF, Singh N, Seddon JM, Lewis RA, Bernstein PS, et al. Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration. Science. 1997;277(5333):1805–7.CrossRefPubMedGoogle Scholar
  4. Annilo, T., Shulenin, S., Chen, Z. Q., Arnould, I., Prades, C., Lemoine, C., … Rosier, M. (2002). Identification and characterization of a novel ABCA subfamily member, ABCA12, located in the lamellar ichthyosis region on 2q34. Cytogenet Genome Res, 98(2–3), 169–176. doi:69811Google Scholar
  5. Annilo T, Chen ZQ, Shulenin S, Dean M. Evolutionary analysis of a cluster of ATP-binding cassette (ABC) genes. Mamm Genome. 2003;14(1):7–20. doi:10.1007/s00335-002-2229-9.CrossRefPubMedGoogle Scholar
  6. Arai E, Sakamoto H, Ichikawa H, Totsuka H, Chiku S, Gotoh M, et al. Multilayer-omics analysis of renal cell carcinoma, including the whole exome, methylome and transcriptome. Int J Cancer. 2014;135(6):1330–42. doi:10.1002/ijc.28768.PubMedCentralCrossRefPubMedGoogle Scholar
  7. Araujo TM, Seabra AD, Lima EM, Assumpcao PP, Montenegro RC, Demachki S, et al. Recurrent amplification of RTEL1 and ABCA13 and its synergistic effect associated with clinicopathological data of gastric adenocarcinoma. Mol Cytogenet. 2016;9:52. doi:10.1186/s13039-016-0260-x.PubMedCentralCrossRefPubMedGoogle Scholar
  8. Baecklund F, Foo JN, Bracci P, Darabi H, Karlsson R, Hjalgrim H, et al. A comprehensive evaluation of the role of genetic variation in follicular lymphoma survival. BMC Med Genet. 2014;15:113. doi:10.1186/s12881-014-0113-6.PubMedCentralCrossRefPubMedGoogle Scholar
  9. Bamji-Mirza M, Li Y, Najem D, Liu QY, Walker D, Lue LF, et al. Genetic variations in ABCA7 can increase secreted levels of amyloid-beta40 and amyloid-beta42 peptides and ABCA7 transcription in cell culture models. J Alzheimers Dis. 2016;53(3):875–92. doi:10.3233/JAD-150965.CrossRefPubMedGoogle Scholar
  10. Barber RC. The genetics of Alzheimer’s disease. Scientifica (Cairo). 2012;2012:246210. doi:10.6064/2012/246210.Google Scholar
  11. Beers MF, Hawkins A, Shuman H, Zhao M, Newitt JL, Maguire JA, et al. A novel conserved targeting motif found in ABCA transporters mediates trafficking to early post-Golgi compartments. J Lipid Res. 2011;52(8):1471–82. doi:10.1194/jlr.M013284.PubMedCentralCrossRefPubMedGoogle Scholar
  12. Biswas-Fiss EE, Kurpad DS, Joshi K, Biswas SB. Interaction of extracellular domain 2 of the human retina-specific ATP-binding cassette transporter (ABCA4) with all-trans-retinal. J Biol Chem. 2010;285(25):19372–83. doi:10.1074/jbc.M110.112896.PubMedCentralCrossRefPubMedGoogle Scholar
  13. Biswas-Fiss EE, Affet S, Ha M, Biswas SB. Retinoid binding properties of nucleotide binding domain 1 of the Stargardt disease-associated ATP binding cassette (ABC) transporter, ABCA4. J Biol Chem. 2012;287(53):44097–107. doi:10.1074/jbc.M112.409623.PubMedCentralCrossRefPubMedGoogle Scholar
  14. Bleasel JM, Hsiao JH, Halliday GM, Kim WS. Increased expression of ABCA8 in multiple system atrophy brain is associated with changes in pathogenic proteins. J Parasit Dis. 2013;3(3):331–9. doi:10.3233/JPD-130203.Google Scholar
  15. Boehm-Cagan A, Bar R, Liraz O, Bielicki JK, Johansson JO, Michaelson DM. ABCA1 agonist reverses the apoE4-driven cognitive and brain pathologies. J Alzheimers Dis. 2016. doi:10.3233/JAD-160467.Google Scholar
  16. Boyer NP, Higbee D, Currin MB, Blakeley LR, Chen C, Ablonczy Z, et al. Lipofuscin and N-retinylidene-N-retinylethanolamine (A2E) accumulate in retinal pigment epithelium in absence of light exposure: their origin is 11-cis-retinal. J Biol Chem. 2012;287(26):22276–86. doi:10.1074/jbc.M111.329235.PubMedCentralCrossRefPubMedGoogle Scholar
  17. Bungert S, Molday LL, Molday RS. Membrane topology of the ATP binding cassette transporter ABCR and its relationship to ABC1 and related ABCA transporters: identification of N-linked glycosylation sites. J Biol Chem. 2001;276(26):23539–46. doi:10.1074/jbc.M101902200.CrossRefPubMedGoogle Scholar
  18. Carrasquillo MM, Belbin O, Hunter TA, Ma L, Bisceglio GD, Zou F, et al. Replication of EPHA1 and CD33 associations with late-onset Alzheimer’s disease: a multi-centre case-control study. Mol Neurodegener. 2011;6(1):54. doi:10.1186/1750-1326-6-54.PubMedCentralCrossRefPubMedGoogle Scholar
  19. Chen P, Dai Y, Wu X, Wang Y, Sun S, Xiao J, et al. Mutations in the ABCA3 gene are associated with cataract-microcornea syndrome. Invest Ophthalmol Vis Sci. 2014;55(12):8031–43. doi:10.1167/iovs.14-14098.CrossRefPubMedGoogle Scholar
  20. Chung SJ, Jung Y, Hong M, Kim MJ, You S, Kim YJ, et al. Alzheimer’s disease and Parkinson’s disease genome-wide association study top hits and risk of Parkinson’s disease in Korean population. Neurobiol Aging. 2013a;34(11):2695.e1–7. doi:10.1016/j.neurobiolaging.2013.05.022.CrossRefGoogle Scholar
  21. Chung SJ, Lee JH, Kim SY, You S, Kim MJ, Lee JY, Koh J. Association of GWAS top hits with late-onset Alzheimer disease in Korean population. Alzheimer Dis Assoc Disord. 2013b;27(3):250–7. doi:10.1097/WAD.0b013e31826d7281.CrossRefPubMedGoogle Scholar
  22. Cui H, Zhang AJ, Chen M, Liu JJ. ABC transporter inhibitors in reversing multidrug resistance to chemotherapy. Curr Drug Targets. 2015;16(12):1356–71.CrossRefPubMedGoogle Scholar
  23. Cukier HN, Kunkle BW, Vardarajan BN, Rolati S, Hamilton-Nelson KL, Kohli MA, et al. ABCA7 frameshift deletion associated with Alzheimer disease in African Americans. Neurol Genet. 2016;2(3):e79. doi:10.1212/NXG.0000000000000079.PubMedCentralCrossRefPubMedGoogle Scholar
  24. Cuyvers E, De Roeck A, Van den Bossche T, Van Cauwenberghe C, Bettens K, Vermeulen S, et al. Mutations in ABCA7 in a Belgian cohort of Alzheimer’s disease patients: a targeted resequencing study. Lancet Neurol. 2015;14(8):814–22. doi:10.1016/S1474-4422(15)00133-7.CrossRefPubMedGoogle Scholar
  25. Davis Jr W. The ATP-binding cassette transporter-2 (ABCA2) regulates esterification of plasma membrane cholesterol by modulation of sphingolipid metabolism. Biochim Biophys Acta. 2014;1841(1):168–79. doi:10.1016/j.bbalip.2013.10.019.CrossRefPubMedGoogle Scholar
  26. Davis Jr W. The ATP-binding cassette transporter-2 (ABCA2) overexpression modulates sphingosine levels and transcription of the Amyloid Precursor Protein (APP) gene. Curr Alzheimer Res. 2015;12(9):847–59.PubMedCentralCrossRefPubMedGoogle Scholar
  27. Dean M, Rzhetsky A, Allikmets R. The human ATP-binding cassette (ABC) transporter superfamily. Genome Res. 2001;11(7):1156–66.CrossRefPubMedGoogle Scholar
  28. Del-Aguila JL, Fernandez MV, Jimenez J, Black K, Ma S, Deming Y, et al. Role of ABCA7 loss-of-function variant in Alzheimer’s disease: a replication study in European-Americans. Alzheimers Res Ther. 2015;7(1):73. doi:10.1186/s13195-015-0154-x.PubMedCentralCrossRefPubMedGoogle Scholar
  29. DeStefano GM, Kurban M, Anyane-Yeboa K, Dall’Armi C, Di Paolo G, Feenstra H, et al. Mutations in the cholesterol transporter gene ABCA5 are associated with excessive hair overgrowth. PLoS Genet. 2014;10(5):e1004333. doi:10.1371/journal.pgen.1004333.PubMedCentralCrossRefPubMedGoogle Scholar
  30. Elsnerova K, Mohelnikova-Duchonova B, Cerovska E, Ehrlichova M, Gut I, Rob L, et al. Gene expression of membrane transporters: importance for prognosis and progression of ovarian carcinoma. Oncol Rep. 2016;35(4):2159–70. doi:10.3892/or.2016.4599.CrossRefPubMedGoogle Scholar
  31. Fasano T, Bocchi L, Pisciotta L, Bertolini S, Calandra S, et al. Denaturing high-performance liquid chromatography in the detection of ABCA1 gene mutations in familial HDL deficiency. J Lipid Res. 2005;46:817–22.doi:10.1194/jlr.D400038-JLR200.Google Scholar
  32. Fitzgerald ML, Okuhira K, Short 3rd GF, Manning JJ, Bell SA, Freeman MW. ATP-binding cassette transporter A1 contains a novel C-terminal VFVNFA motif that is required for its cholesterol efflux and ApoA-I binding activities. J Biol Chem. 2004;279(46):48477–85. doi:10.1074/jbc.M409848200.CrossRefPubMedGoogle Scholar
  33. Fitzgerald ML, Mujawar Z, Tamehiro N. ABC transporters, atherosclerosis and inflammation. Atherosclerosis. 2010;211(2):361–70. doi:10.1016/j.atherosclerosis.2010.01.011.PubMedCentralCrossRefPubMedGoogle Scholar
  34. Fu Y, Hsiao JH, Paxinos G, Halliday GM, Kim WS. ABCA5 regulates amyloid-beta peptide production and is associated with Alzheimer’s disease neuropathology. J Alzheimers Dis. 2015;43(3):857–69. doi:10.3233/JAD-141320.PubMedGoogle Scholar
  35. Fu Y, Hsiao JH, Paxinos G, Halliday GM, Kim WS. ABCA7 mediates phagocytic clearance of amyloid-beta in the brain. J Alzheimers Dis. 2016;54(2):569–84. doi:10.3233/JAD-160456.CrossRefPubMedGoogle Scholar
  36. Gai J, Ji M, Shi C, Li W, Chen S, Wang Y, Li H. FoxO regulates expression of ABCA6, an intracellular ATP-binding-cassette transporter responsive to cholesterol. Int J Biochem Cell Biol. 2013;45(11):2651–9. doi:10.1016/j.biocel.2013.08.020.CrossRefPubMedGoogle Scholar
  37. Gao Y, Li W, Liu X, Gao F, Zhao X. Reversing effect and mechanism of soluble resistance-related calcium-binding protein on multidrug resistance in human lung cancer A549/DDP cells. Mol Med Rep. 2015;11(3):2118–24. doi:10.3892/mmr.2014.2936.CrossRefPubMedGoogle Scholar
  38. Hafler BP. Clinical progress in inherited retinal degenerations: gene therapy clinical trials and advances in genetic sequencing. Retina. 2016. doi:10.1097/IAE.0000000000001341.Google Scholar
  39. Hedditch EL, Gao B, Russell AJ, Lu Y, Emmanuel C, Beesley J, et al. ABCA transporter gene expression and poor outcome in epithelial ovarian cancer. J Natl Cancer Inst. 2014;106(7). doi:10.1093/jnci/dju149.Google Scholar
  40. Higgins CF. ABC transporters: physiology, structure and mechanism – an overview. Res Microbiol. 2001;152(3–4):205–10.CrossRefPubMedGoogle Scholar
  41. Hohman TJ, Cooke-Bailey JN, Reitz C, Jun G, Naj A, Beecham GW, et al. Global and local ancestry in African-Americans: implications for Alzheimer’s disease risk. Alzheimers Dement. 2016;12(3):233–43. doi:10.1016/j.jalz.2015.02.012.CrossRefPubMedGoogle Scholar
  42. Iatan I, Bailey D, Ruel I, Hafiane A, Campbell S, Krimbou L, Genest J. Membrane microdomains modulate ligand binding activity of oligomeric ABCA1 and apoA-I-mediated lipid removal: molecular evidence that ApoA-I interaction with ABCA1 activates the phosphatidylcholine biosynthesis pathway. J Lipid Res. 2011. doi:10.1194/jlr.M016196.PubMedCentralPubMedGoogle Scholar
  43. Ingram WJ, Crowther LM, Little EB, Freeman R, Harliwong I, Veleva D, et al. ABC transporter activity linked to radiation resistance and molecular subtype in pediatric medulloblastoma. Exp Hematol Oncol. 2013;2(1):26. doi:10.1186/2162-3619-2-26.PubMedCentralCrossRefPubMedGoogle Scholar
  44. Januchowski R, Zawierucha P, Andrzejewska M, Rucinski M, Zabel M. Microarray-based detection and expression analysis of ABC and SLC transporters in drug-resistant ovarian cancer cell lines. Biomed Pharmacother. 2013;67(3):240–5. doi:10.1016/j.biopha.2012.11.011.CrossRefPubMedGoogle Scholar
  45. Januchowski R, Zawierucha P, Rucinski M, Andrzejewska M, Wojtowicz K, Nowicki M, Zabel M. Drug transporter expression profiling in chemoresistant variants of the A2780 ovarian cancer cell line. Biomed Pharmacother. 2014;68(4):447–53. doi:10.1016/j.biopha.2014.02.002.CrossRefPubMedGoogle Scholar
  46. Kaminski WE, Piehler A, Wenzel JJ. ABC A-subfamily transporters: structure, function and disease. Biochim Biophys Acta. 2006;1762(5):510–24. doi:10.1016/j.bbadis.2006.01.011.CrossRefPubMedGoogle Scholar
  47. Karatas OF, Guzel E, Duz MB, Ittmann M, Ozen M. The role of ATP-binding cassette transporter genes in the progression of prostate cancer. Prostate. 2016;76(5):434–44. doi:10.1002/pros.23137.CrossRefPubMedGoogle Scholar
  48. Kim WS, Halliday GM. Changes in sphingomyelin level affect alpha-synuclein and ABCA5 expression. J Parasit Dis. 2012;2(1):41–6. doi:10.3233/JPD-2012-11059.Google Scholar
  49. Kim WS, Weickert CS, Garner B. Role of ATP-binding cassette transporters in brain lipid transport and neurological disease. J Neurochem. 2008;104(5):1145–66. doi:10.1111/j.1471-4159.2007.05099.x.CrossRefPubMedGoogle Scholar
  50. Kim WS, Hsiao JH, Bhatia S, Glaros EN, Don AS, Tsuruoka S, et al. ABCA8 stimulates sphingomyelin production in oligodendrocytes. Biochem J. 2013;452(3):401–10. doi:10.1042/BJ20121764.CrossRefPubMedGoogle Scholar
  51. Knight HM, Pickard BS, Maclean A, Malloy MP, Soares DC, McRae AF, et al. A cytogenetic abnormality and rare coding variants identify ABCA13 as a candidate gene in schizophrenia, bipolar disorder, and depression. Am J Hum Genet. 2009;85(6):833–46. doi:10.1016/j.ajhg.2009.11.003.PubMedCentralCrossRefPubMedGoogle Scholar
  52. Koochek A, Choate KA, Milstone LM. Harlequin ichthyosis: neonatal management and identification of a new ABCA12 mutation. Pediatr Dermatol. 2014;31(2):e63–4. doi:10.1111/pde.12263.CrossRefPubMedGoogle Scholar
  53. Lane TS, Rempe CS, Davitt J, Staton ME, Peng Y, Soltis DE, et al. Diversity of ABC transporter genes across the plant kingdom and their potential utility in biotechnology. BMC Biotechnol. 2016;16(1):47. doi:10.1186/s12896-016-0277-6.PubMedCentralCrossRefPubMedGoogle Scholar
  54. Liao YC, Lee WJ, Hwang JP, Wang YF, Tsai CF, Wang PN, et al. ABCA7 gene and the risk of Alzheimer’s disease in Han Chinese in Taiwan. Neurobiol Aging. 2014;35(10):2423.e7–13. doi:10.1016/j.neurobiolaging.2014.05.009.CrossRefGoogle Scholar
  55. Liu X, Gao Y, Zhao B, Li X, Lu Y, Zhang J, et al. Discovery of microarray-identified genes associated with ovarian cancer progression. Int J Oncol. 2015;46(6):2467–78. doi:10.3892/ijo.2015.2971.PubMedGoogle Scholar
  56. Logue MW, Schu M, Vardarajan BN, Buros J, Green RC, Go RC, et al. A comprehensive genetic association study of Alzheimer disease in African Americans. Arch Neurol. 2011;68(12):1569–79. doi:10.1001/archneurol.2011.646.PubMedCentralCrossRefPubMedGoogle Scholar
  57. Ma J, Lan X, Gao N, Wang J, Hao D, Yao J, et al. A genetic association study between common variants in the ABCA13 gene and schizophrenia in a Han Chinese population. Psychiatry Res. 2013;209(3):748–9. doi:10.1016/j.psychres.2013.07.013.CrossRefPubMedGoogle Scholar
  58. Mace S, Cousin E, Ricard S, Genin E, Spanakis E, Lafargue-Soubigou C, et al. ABCA2 is a strong genetic risk factor for early-onset Alzheimer’s disease. Neurobiol Dis. 2005;18(1):119–25. doi:10.1016/j.nbd.2004.09.011.CrossRefPubMedGoogle Scholar
  59. Mack JT, Beljanski V, Tew KD, Townsend DM. The ATP-binding cassette transporter ABCA2 as a mediator of intracellular trafficking. Biomed Pharmacother. 2006;60(9):587–92. doi:10.1016/j.biopha.2006.07.090.CrossRefPubMedGoogle Scholar
  60. Mack JT, Brown CB, Garrett TE, Uys JD, Townsend DM, Tew KD. Ablation of the ATP-binding cassette transporter, Abca2 modifies response to estrogen-based therapies. Biomed Pharmacother. 2012;66(6):403–8. doi:10.1016/j.biopha.2012.06.007.PubMedCentralCrossRefPubMedGoogle Scholar
  61. Mata NL, Tzekov RT, Liu X, Weng J, Birch DG, Travis GH. Delayed dark-adaptation and lipofuscin accumulation in abcr+/− mice: implications for involvement of ABCR in age-related macular degeneration. Invest Ophthalmol Vis Sci. 2001;42(8):1685–90.PubMedGoogle Scholar
  62. Matsuzaki Y, Besnard V, Clark JC, Xu Y, Wert SE, Ikegami M, Whitsett JA. STAT3 regulates ABCA3 expression and influences lamellar body formation in alveolar type II cells. Am J Respir Cell Mol Biol. 2008;38(5):551–8. doi:10.1165/rcmb.2007-0311OC.CrossRefPubMedGoogle Scholar
  63. Michaki V, Guix FX, Vennekens K, Munck S, Dingwall C, Davis JB, et al. Down-regulation of the ATP-binding cassette transporter 2 (Abca2) reduces amyloid-beta production by altering Nicastrin maturation and intracellular localization. J Biol Chem. 2012;287(2):1100–11. doi:10.1074/jbc.M111.288258.CrossRefPubMedGoogle Scholar
  64. Molday RS, Beharry S, Ahn J, Zhong M. Binding of N-retinylidene-PE to ABCA4 and a model for its transport across membranes. Adv Exp Med Biol. 2006;572:465–70.CrossRefPubMedGoogle Scholar
  65. Nordestgaard LT, Tybjaerg-Hansen A, Nordestgaard BG, Frikke-Schmidt R. Loss-of-function mutation in ABCA1 and risk of Alzheimer’s disease and cerebrovascular disease. Alzheimers Dement. 2015;11(12):1430–8. doi:10.1016/j.jalz.2015.04.006.CrossRefPubMedGoogle Scholar
  66. Nuytemans K, Maldonado L, Ali A, John-Williams K, Beecham GW, Martin E, et al. Overlap between Parkinson disease and Alzheimer disease in ABCA7 functional variants. Neurol Genet. 2016;2(1):e44. doi:10.1212/NXG.0000000000000044.PubMedCentralCrossRefPubMedGoogle Scholar
  67. Nymoen DA, Holth A, Hetland Falkenthal TE, Trope CG, Davidson B. CIAPIN1 and ABCA13 are markers of poor survival in metastatic ovarian serous carcinoma. Mol Cancer. 2015;14:44. doi:10.1186/s12943-015-0317-1.PubMedCentralCrossRefPubMedGoogle Scholar
  68. Ohtsuki S, Kamoi M, Watanabe Y, Suzuki H, Hori S, Terasaki T. Correlation of induction of ATP binding cassette transporter A5 (ABCA5) and ABCB1 mRNAs with differentiation state of human colon tumor. Biol Pharm Bull. 2007;30(6):1144–6.CrossRefPubMedGoogle Scholar
  69. Ordovas JM. ABC1: the gene for Tangier disease and beyond. Nutr Rev. 2000;58(3 Pt 1):76–9.PubMedGoogle Scholar
  70. Peca D, Cutrera R, Masotti A, Boldrini R, Danhaive O. ABCA3, a key player in neonatal respiratory transition and genetic disorders of the surfactant system. Biochem Soc Trans. 2015;43(5):913–9. doi:10.1042/BST20150100.CrossRefPubMedGoogle Scholar
  71. Peelman F, Labeur C, Vanloo B, Roosbeek S, Devaud C, Duverger N, et al. Characterization of the ABCA transporter subfamily: identification of prokaryotic and eukaryotic members, phylogeny and topology. J Mol Biol. 2003;325(2):259–74.CrossRefPubMedGoogle Scholar
  72. Pickard BS, Van Den Bossche MJ, Malloy MP, Johnstone M, Lenaerts AS, Nordin A, et al. Multiplex amplicon quantification screening the ABCA13 gene for copy number variation in schizophrenia and bipolar disorder. Psychiatr Genet. 2012;22(5):269–70. doi:10.1097/YPG.0b013e32835185b3.CrossRefPubMedGoogle Scholar
  73. Pollock NL, Callaghan R. The lipid translocase, ABCA4: seeing is believing. FEBS J. 2011;278(18):3204–14. doi:10.1111/j.1742-4658.2011.08169.x.CrossRefPubMedGoogle Scholar
  74. Prades C, Arnould I, Annilo T, Shulenin S, Chen ZQ, Orosco L, et al. The human ATP binding cassette gene ABCA13, located on chromosome 7p12.3, encodes a 5058 amino acid protein with an extracellular domain encoded in part by a 4.8-kb conserved exon. Cytogenet Genome Res. 2002;98(2–3):160–8. doi:10.1159/000069852.CrossRefPubMedGoogle Scholar
  75. Rahgozar S, Moafi A, Abedi M, Entezar EGM, Moshtaghian J, Ghaedi K, et al. mRNA expression profile of multidrug-resistant genes in acute lymphoblastic leukemia of children, a prognostic value for ABCA3 and ABCA2. Cancer Biol Ther. 2014;15(1):35–41. doi:10.4161/cbt.26603.CrossRefPubMedGoogle Scholar
  76. Rickels MR, Goeser ES, Fuller C, Lord C, Bowler AM, Doliba NM, et al. Loss-of-function mutations in ABCA1 and enhanced beta-cell secretory capacity in young adults. Diabetes. 2015;64(1):193–9. doi:10.2337/db14-0436.CrossRefPubMedGoogle Scholar
  77. Saini V, Hose CD, Monks A, Nagashima K, Han B, Newton DL, et al. Identification of CBX3 and ABCA5 as putative biomarkers for tumor stem cells in osteosarcoma. PLoS One. 2012;7(8):e41401. doi:10.1371/journal.pone.0041401.PubMedCentralCrossRefPubMedGoogle Scholar
  78. Schulz V, Hendig D, Henjakovic M, Szliska C, Kleesiek K, Gotting C. Mutational analysis of the ABCC6 gene and the proximal ABCC6 gene promoter in German patients with pseudoxanthoma elasticum (PXE). Hum Mutat. 2006;27(8):831. doi:10.1002/humu.9444.CrossRefPubMedGoogle Scholar
  79. Shi H, Belbin O, Medway C, Brown K, Kalsheker N, Carrasquillo M, et al. Genetic variants influencing human aging from late-onset Alzheimer’s disease (LOAD) genome-wide association studies (GWAS). Neurobiol Aging. 2012;33(8):1849.5–18. doi:10.1016/j.neurobiolaging.2012.02.014.CrossRefGoogle Scholar
  80. Steinberg S, Stefansson H, Jonsson T, Johannsdottir H, Ingason A, Helgason H, et al. Loss-of-function variants in ABCA7 confer risk of Alzheimer’s disease. Nat Genet. 2015;47(5):445–7. doi:10.1038/ng.3246.CrossRefPubMedGoogle Scholar
  81. Stenirri S, Battistella S, Fermo I, Manitto MP, Martina E, Brancato R, et al. De novo deletion removes a conserved motif in the C-terminus of ABCA4 and results in cone-rod dystrophy. Clin Chem Lab Med. 2006;44(5):533–7. doi:10.1515/CCLM.2006.116.CrossRefPubMedGoogle Scholar
  82. Takahashi K, Kimura Y, Nagata K, Yamamoto A, Matsuo M, Ueda K. ABC proteins: key molecules for lipid homeostasis. Med Mol Morphol. 2005;38(1):2–12. doi:10.1007/s00795-004-0278-8.CrossRefPubMedGoogle Scholar
  83. Tan L, Yu JT, Zhang W, Wu ZC, Zhang Q, Liu QY, et al. Association of GWAS-linked loci with late-onset Alzheimer’s disease in a northern Han Chinese population. Alzheimers Dement. 2013;9(5):546–53. doi:10.1016/j.jalz.2012.08.007.CrossRefPubMedGoogle Scholar
  84. Tan WJ, Cima I, Choudhury Y, Wei X, Lim JC, Thike AA, et al. A five-gene reverse transcription-PCR assay for pre-operative classification of breast fibroepithelial lesions. Breast Cancer Res. 2016;18(1):31. doi:10.1186/s13058-016-0692-6.PubMedCentralCrossRefPubMedGoogle Scholar
  85. Tanaka AR, Abe-Dohmae S, Ohnishi T, Aoki R, Morinaga G, Okuhira K, et al. Effects of mutations of ABCA1 in the first extracellular domain on subcellular trafficking and ATP binding/hydrolysis. J Biol Chem. 2003;278(10):8815–9. doi:10.1074/jbc.M206885200.CrossRefPubMedGoogle Scholar
  86. Tanaka N, Abe-Dohmae S, Iwamoto N, Yokoyama S, et al. Roles of ATP-binding cassette transporter A7 in cholesterol homeostasis and host defense system. J Atheroscler Thromb. 2011;18:274–81. doi:10.5551/jat.6726Google Scholar
  87. Theodoulou FL, Kerr ID. ABC transporter research: going strong 40 years on. Biochem Soc Trans. 2015;43(5):1033–40. doi:10.1042/BST20150139.PubMedCentralCrossRefPubMedGoogle Scholar
  88. Tsybovsky Y, Molday RS, Palczewski K. The ATP-binding cassette transporter ABCA4: structural and functional properties and role in retinal disease. Adv Exp Med Biol. 2010;703:105–25. doi:10.1007/978-1-4419-5635-4_8.PubMedCentralCrossRefPubMedGoogle Scholar
  89. Turcu S, Ashton E, Jenkins L, Gupta A, Mok Q. Genetic testing in children with surfactant dysfunction. Arch Dis Child. 2013;98(7):490–5. doi:10.1136/archdischild-2012-303166.CrossRefPubMedGoogle Scholar
  90. Van den Bossche T, Sleegers K, Cuyvers E, Engelborghs S, Sieben A, De Roeck A, et al. Phenotypic characteristics of Alzheimer patients carrying an ABCA7 mutation. Neurology. 2016;86(23):2126–33. doi:10.1212/WNL.0000000000002628.PubMedCentralCrossRefPubMedGoogle Scholar
  91. van der Deen M, de Vries EG, Timens W, Scheper RJ, Timmer-Bosscha H, Postma DS. ATP-binding cassette (ABC) transporters in normal and pathological lung. Respir Res. 2005;6:59. doi:10.1186/1465-9921-6-59.PubMedCentralCrossRefPubMedGoogle Scholar
  92. van Leeuwen EM, Karssen LC, Deelen J, Isaacs A, Medina-Gomez C, Mbarek H, et al. Genome of The Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels. Nat Commun. 2015;6:6065. doi:10.1038/ncomms7065.PubMedCentralCrossRefPubMedGoogle Scholar
  93. Vasiliou V, Vasiliou K, Nebert DW. Human ATP-binding cassette (ABC) transporter family. Hum Genomics. 2009;3(3):281–90.PubMedCentralCrossRefPubMedGoogle Scholar
  94. Wakino S, Itoh H. Anti-atherosclerotic effects by PPARgamma and its ligands through the activation of reverse cholesterol transport system. Nihon Rinsho. 2010;68(2):217–23.PubMedGoogle Scholar
  95. Wang N, Lan D, Gerbod-Giannone M, Linsel-Nitschke P, Jehle AW, Chen W, et al. ATP-binding cassette transporter A7 (ABCA7) binds apolipoprotein A-I and mediates cellular phospholipid but not cholesterol efflux. J Biol Chem. 2003;278(44):42906–12. doi:10.1074/jbc.M307831200.CrossRefPubMedGoogle Scholar
  96. Wenzel JJ, Piehler A, Kaminski WE. ABC A-subclass proteins: gatekeepers of cellular phospho- and sphingolipid transport. Front Biosci. 2007;12:3177–93.CrossRefPubMedGoogle Scholar
  97. Wert SE, Whitsett JA, Nogee LM. Genetic disorders of surfactant dysfunction. Pediatr Dev Pathol. 2009;12(4):253–74. doi:10.2350/09-01-0586.1.PubMedCentralCrossRefPubMedGoogle Scholar
  98. Wong JH, Halliday GM, Kim WS. Exploring myelin dysfunction in multiple system atrophy. Exp Neurobiol. 2014;23(4):337–44. doi:10.5607/en.2014.23.4.337.PubMedCentralCrossRefPubMedGoogle Scholar
  99. Xie N, Chen DH, Lin YN, Wu SZ, Gu YY, Zeng QS, et al. Pulmonary surfactant protein adenosine triphosphate-binding-cassette-A3 gene composite mutations in infant congenital interstitial lung disease: report of a case and review of literature. Zhonghua Er Ke Za Zhi. 2016a;54(10):761–6. doi:10.3760/cma.j.issn.0578-1310.2016.10.010.PubMedGoogle Scholar
  100. Xie H, Xie Y, Peng R, Li L, Zhu Y, Guo J. Harlequin ichthyosis: a novel compound mutation of ABCA12 with prenatal diagnosis. Clin Exp Dermatol. 2016b;41(6):636–9. doi:10.1111/ced.12861.CrossRefPubMedGoogle Scholar
  101. Yassine HN, Feng Q, Chiang J, Petrosspour LM, Fonteh AN, Chui HC, Harrington MG. ABCA1-mediated cholesterol efflux capacity to cerebrospinal fluid is reduced in patients with mild cognitive impairment and Alzheimer’s disease. J Am Heart Assoc. 2016;5(2). doi:10.1161/JAHA.115.002886.Google Scholar
  102. Yu Y, Reynolds R, Fagerness J, Rosner B, Daly MJ, Seddon JM. Association of variants in the LIPC and ABCA1 genes with intermediate and large drusen and advanced age-related macular degeneration. Invest Ophthalmol Vis Sci. 2011;52(7):4663–70. doi:10.1167/iovs.10-7070.PubMedCentralCrossRefPubMedGoogle Scholar
  103. Yu L, Chibnik LB, Srivastava GP, Pochet N, Yang J, Xu J, et al. Association of Brain DNA methylation in SORL1, ABCA7, HLA-DRB5, SLC24A4, and BIN1 with pathological diagnosis of Alzheimer disease. JAMA Neurol. 2015;72(1):15–24. doi:10.1001/jamaneurol.2014.3049.PubMedCentralCrossRefPubMedGoogle Scholar
  104. Zhang L, Ferreyros M, Feng W, Hupe M, Crumrine DA, Chen J, et al. Defects in stratum corneum desquamation are the predominant effect of impaired ABCA12 function in a novel mouse model of harlequin ichthyosis. PLoS One. 2016;11(8):e0161465. doi:10.1371/journal.pone.0161465.PubMedCentralCrossRefPubMedGoogle Scholar
  105. Zhao QF, Yu JT, Tan MS, Tan L. ABCA7 in Alzheimer’s disease. Mol Neurobiol. 2015;51(3):1008–16. doi:10.1007/s12035-014-8759-9.CrossRefPubMedGoogle Scholar
  106. Zhong M, Molday LL, Molday RS. Role of the C terminus of the photoreceptor ABCA4 transporter in protein folding, function, and retinal degenerative diseases. J Biol Chem. 2009;284(6):3640–9. doi:10.1074/jbc.M806580200.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Esther E. Biswas-Fiss
    • 1
    • 2
  • Albtool Alturkestani
    • 1
  • Jazzlyn Jones
    • 1
  • Joscelyn Korth
    • 1
  • Stephanie Affet
    • 3
  • Malissa Ha
    • 3
  • Subhasis Biswas
    • 4
  1. 1.Department of Medical Laboratory Sciences, College of Health SciencesUniversity of DelawareNewarkUSA
  2. 2.Department of Molecular BiologyRowan University School of Osteopathic MedicineStratfordUSA
  3. 3.Department of Bioscience Technologies, Program in Biotechnology, JSHPThomas Jefferson UniversityPhiladelphiaUSA
  4. 4.Department of Molecular BiologyRowan UniversityStratfordUSA