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Biochimica et Biophysica Acta 1762 (2006) 510–524 http://www.elsevier.com/locate/bba

Review ABC A-subfamily transporters: Structure, function and disease ⁎ Wolfgang E. Kaminski a, , Armin Piehler b, Jürgen J. Wenzel c

a Institute for Clinical Chemistry, Faculty for Clinical Medicine Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany b Department of Clinical Chemistry, Ulleval University Hospital, 0407 Oslo, Norway c Department of Medicine II, Johannes Gutenberg-University Mainz, 55101 Mainz, Germany Received 24 October 2005; received in revised form 30 January 2006; accepted 31 January 2006 Available online 28 February 2006

Abstract

ABC transporters constitute a family of evolutionarily highly conserved multispan proteins that mediate the translocation of defined substrates across membrane barriers. Evidence has accumulated during the past years to suggest that a subgroup of 12 structurally related “full-size” transporters, referred to as ABC A-subfamily transporters, mediates the transport of a variety of physiologic lipid compounds. The emerging importance of ABC A-transporters in human disease is reflected by the fact that as yet four members of this protein family (ABCA1, ABCA3, ABCR/ABCA4, ABCA12) have been causatively linked to completely unrelated groups of monogenetic disorders including familial high-density lipoprotein (HDL) deficiency, neonatal surfactant deficiency, degenerative retinopathies and congenital keratinization disorders. Although the biological function of the remaining 8 ABC A-transporters currently awaits clarification, they represent promising candidate genes for a presumably equally heterogenous group of Mendelian diseases associated with perturbed cellular lipid transport. This review summarizes our current knowledge on the role of ABC A-subfamily transporters in physiology and disease and explores clinical entities which may be potentially associated with dysfunctional members of this gene subfamily. © 2006 Elsevier B.V. All rights reserved.

Keywords: ABC transporter; Lipid; Atherosclerosis; Retina; Surfactant; Ichthyosis

1. Introduction human family of ABC transporters have been identified which, based on their structural relatedness, are subdivided into 7 ATP-binding cassette (ABC) transporters constitute one of families, designated ABC A–G [1]. the largest known superfamilies of proteins [1].These Functional ABC transporters show a common global evolutionary highly conserved multispan transmembrane mole- organization. So-called full-size ABC transporters are typically cules use the energy of ATP hydrolysis to translocate a broad composed of two tandemly linked functional units [3], each spectrum of molecules across the cell membrane. Substrates that consisting of an ATP binding cassette and a transmembrane are transported by ABC molecules include lipids, peptides, domain complex. Alternatively, they can form homo- or amino acids, carbohydrates, vitamins, ions, glucuronide and heterodimers which consist of two half-size transporters that glutathione conjugates, and xenobiotics [1,2]. In eukaryotes, are encoded by distinct genes [4]. Evidence has accumulated to ABC transporters are located in the plasma membrane, in the suggest that ABC transporters exert their functions as membranes of intracellular compartments such as the Golgi, membrane associated multiunit complexes. Examples include endosome, multivesicular bodies, endoplasmic reticulum, the ABC transporter ABCC8 (SUR1) which is functionally peroxisome, and in mitochondria. To date, 48 members of the associated with the K+ channel KIR6.1 and a potassium- sensitive Ca2+-channel [5,6]. Moreover, the transporter CFTR (ABCC7) binds syntaxin 1A, a member of the syntaxin family of membrane fusion regulators [7], a sodium channel [8] and the ⁎ Corresponding author. Tel.: +49 0621 383 4012; fax: +49 0621 383 3819. endocytic adaptor complex AP-2 [9]. It is thus conceivable that E-mail address: [email protected] full-size ABC transporters, as large components of membrane (W.E. Kaminski). associated multiunit complexes, are not necessarily restricted to

0925-4439/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.bbadis.2006.01.011 W.E. Kaminski et al. / Biochimica et Biophysica Acta 1762 (2006) 510–524 511 serve one defined function but are likely involved in a spectrum cluster on chromosome 17q, it has been suggested that these of biologic activities depending on the specific assembly of the five transporters represent a separate subgroup within the A- functional complex and the biologic activities of their subfamily (“ABCA6-like transporters”) [11,12]. interaction partners. 3. ABC A-subclass transporters causing inherited diseases 2. Structural and evolutionary features of human ABC A-subclass transporters In the 1990s, considerable efforts have been made to study the role of ABC transporters in multidrug resistance in the ABCA1 and ABCA2 (formerly known as ABC1 and context of tumor cell therapy. However, the bona fide biological ABC2, respectively), the prototypic members of the ABC A- functions of most known ABC transporters remained and still subfamily, were initially co-identified by Luciani et al. [10] in remain unclear. In recent years, a series of groundbreaking the mouse. Throughout the past decade, 10 additional studies has dramatically expanded our knowledge of the role of functional genes were discovered. Based on their common ABC molecules in physiology and disease and has led to the structural features, which set them apart from other ABC systematic identification of all members of the human ABC transporters, they were categorized into a distinct subgroup— transporter gene family. the ABC A-subfamily [1]. The known 12 human ABC A- Assessment of the biological role of full-size ABC trans- transporters have been denoted ABCA1–ABCA13. The porters is a difficult task because of the complex architecture of current nomenclature is inconsistent in that since no these large molecules, their strategic position between two functional human “ABCA11” gene exists (a designation that compartments that are separated by lipid bilayers and the fact has originally been erroneously assigned to a pseudogene). that they appear to operate as part of membrane bound Structurally, all ABC A-transporters are full-size transporters multifunction complexes. Most valuable insights into their that range from 1543 to 5058 amino acids (aa) in size. A physiologic functions come from loss of function scenarios as synopsis of their biological features is shown in Table 1. With they occur in human monogenetic diseases and genetically the exception of ABCR, which is selectively expressed in the modified null mutant mice. To date, loss of function mutations retina, and ABCA13, whose expression appears to be limited in 14 ABC transporters have been causatively linked to to a small number of organs, ABC A-transporters have broad Mendelian disorders (Table 3). Interestingly, among human tissue-specificity. ABC transporters outside the A-subfamily a striking tropism Pairwise comparison of the amino acid sequences of all can be observed for diseases that manifest with defective known 12 human ABC A-subfamily members reveals exocrine/endocrine function in the liver–pancreas system. homologies ranging from 28% (ABCA8/ABCA12) to 72% These include disorders associated with dysfunctional bile (ABCA8/ABCA9) (Table 2). Phylogenetic analysis suggests secretion (progressive familial intrahepatic cholestasis types 2 that all ABC A-subclass genes have evolved from a and 3, and Dubin–Johnson syndrome caused by defective primordial ancestor gene and were subsequently dispersed ABCB4, ABCB11, and ABCC2, respectively), cystic fibrosis across the genome (Fig. 1) [1]. Of note, the transporters (CFTR/ABCC7) and familial hyperinsulinism (ABCC8) [13– ABCA5, ABCA6, ABCA8, ABCA9, and ABCA10 share 15]. Moreover, the ABC C-subfamily transporter ABCC6, strikingly high overall amino acid sequence homologies but mutations of which mainly cause a skin phenotype known as differ significantly from other ABC A-subfamily members. pseudoxanthoma elasticum, is strongly expressed in the liver Based on this and the fact that their genes form a compact and calcifications in the pancreas have also been reported [16].

Table 1 Biological features of ABC A-transporters Gene GenBank Chrom. Gene Exons Alt. spliced Cholesterol Amino Molecular accession no. localization size (kb) mRNAs responsiveness acids weight (kDa) ABCA1 NM_005502 9q31.1 147 50 nr + 2261 254 ABCA2 NM_001606 9q34.3 21 48 nr + 2436 270 ABCA3 NM_001089 16p13.3 65 33 nr ? 1704 191 ABCA4 NM_000350 1p22.1 128 50 nr − 2273 256 ABCA5 NM_018672 17q24.3 69 38 nr ? 1642 187 ABCA6 NM_080284 17q24.2–3 63 39 1 + 1617 184 ABCA7 NM_019112 19p13.3 24 46 2 + 2146 235 ABCA8 NM_007168 17q24.2 88 38 nr ? 1581 179 ABCA9 NM_080283 17q24.2 86 39 3 + 1624 184 ABCA10 NM_080282 17q24.3 97 40 4 + 1543 176 ABCA12 NM_173076 2q35 207 53 2 ? 2595 293 ABCA13 NM_152701 7p12.3 449 60 5 ? 5058 576 Accession numbers refer to the NCBI GenBank, chromsomal localizations to the UCSC Genome browser (http://genome.ucsc.edu). Gene sizes and exon numbers were determined on the basis of the respective complete cDNAs using the UCSC Genome browser (NCBI/UCSC Build 35, May 2004) and confirmed by BLAT and SIM4 alignments, respectively. Amino acid numbers and molecular weights were calculated with the EMBOSS program “pepstats”. Note the absence of a functional “ABCA11” gene; nr, not reported. 512 W.E. Kaminski et al. / Biochimica et Biophysica Acta 1762 (2006) 510–524

Table 2 Pairwise amino acid sequence similarities/identities (%) between human ABC A-transporters CDS ABCA1 ABCA2 ABCA3 ABCA4 ABCA5 ABCA6 ABCA7 ABCA8 ABCA9 ABCA10 ABCA12 ABCA13 ABCA1 100/100 ABCA2 54/46 100/100 ABCA3 51/41 51/41 100/100 ABCA4 60/52 50/40 49/39 100/100 ABCA5 41/31 42/31 41/30 41/30 100/100 ABCA6 43/31 42/31 40/29 41/31 53/43 100/100 ABCA7 63/54 50/41 49/39 58/49 40/29 39/29 100/100 ABCA8 42/31 43/32 42/32 41/30 53/42 67/60 41/31 100/100 ABCA9 41/31 41/31 43/33 41/30 53/43 68/60 42/32 78/72 100/100 ABCA10 42/31 42/32 41/30 41/29 54/44 70/63 41/29 69/62 71/63 100/100 ABCA12 47/36 44/34 47/35 46/35 41/28 39/28 47/36 40/28 40/28 41/30 100/100 ABCA13 47/36 44/35 45/35 46/35 40/30 40/30 45/36 41/31 39/29 40/30 47/38 100/100 Percentages of overall amino acid sequence similarities and identities were assessed utilizing the GAP software (GCG, HUSAR, DKFZ, Heidelberg, Germany), CDS, coding sequence.

Molecular and pathophysiological aspects of these transporters When looking at the topological distribution of known have been extensively reviewed by others (for reference see mutations within the ABCA1 protein product, two findings [13–15,17]). In this article, we will primarily focus on the are of note. First, mutations within the ABCA1 gene appear to biology of A-subclass ABC transporters and their various occur in clusters. Major mutation clusters can be found in the C- implications in disease. terminal moiety of the first extracellular domain, the N-terminal ATP binding cassette and the C-terminus. Secondly, mutations 3.1. ABCA1-familial HDL-deficiency syndromes and in the first extracellular domain and the C-terminus mutations atherogenesis are frequently associated with a cardiovascular phenotype. In contrast, amino acid exchanges in or in the proximity of the N- ABCA1 is the defining member of the A-subclass of ABC terminal ATP binding cassette appear to coincide with proteins. It is expressed in a multitude of human organs with splenomegaly. These observations raise the possibility that highest expression levels in placenta, liver, lung, adrenal amino acid substitutions within a few selected domains of the glands and fetal tissues [18]. ABCA1 is upregulated by ABCA1 protein may, to a significant degree, determine the type cholesterol influx in macrophages and suppressed by HDL3 of clinical presentation. In light of this, one may postulate a mediated cholesterol efflux [18]—a characteristic feature that critical function for the C-terminal moiety of the first it shares with other ABC A-subfamily transporters (Table 1). extracellular domain and the C-terminus in the development The human cDNA codes for a 2261-amino acid polypeptide of the cardiovascular phenotype. with a molecular weight of 220 kDa [18,19]. ABCA1 shows Because TD is a very rare disease, it is uncertain to what highest amino acid homology with ABCA7 (54%) [20] and extent allelic variants in the ABCA1 gene affect HDL levels in the retina-specific ABCA4 (52%), respectively [21,22]. After the general population. A number of studies have reported the identification of ABCA1 in 1994 [10], only little was polymorphisms in the coding and non-coding regions of known about the biologic function of ABCA1 for quite some ABCA1 that are associated with increased risk for cardiovas- time. The major breakthrough came 5 years later when we cular disease (CAD) [28–31]. In particular, a recent study in a and others discovered that mutations in the human ABCA1 large Caucasian cohort suggests that at least 10% of individuals gene are the underlying molecular defect in familial high- with low HDL cholesterol are heterozygous for mutations in density lipoprotein (HDL)-deficiency syndromes (Tangier ABCA1 and that both mutations and allelic variants in this gene disease, TD) which identified ABCA1 as a major regulator contribute to HDL levels in the general population [32]. On the of HDL metabolism [23–25].TDisarareautosomal other hand, one dimorphism in the ABCA1 gene, R219K, recessive disorder of lipid metabolism characterized by almost appears to exert atheroprotective effects [30]. At this point, complete absence of plasma HDL and the accumulation of however, it remains unclear whether single allelic variants in the cholesteryl esters in the cells of the reticulo-endothelial ABCA1 gene are indeed useful risk predictors in CAD. Since it system leading to splenomegaly and enlargement of tonsils is realistic to assume that ABCA1, like other full-size ABC and lymph nodes [26]. Consistent with the finding that transporters, functions as component of a membrane associated mutations in ABCA1 cause an HDL deficiency phenotype in higher order functional complex, specific emphasis needs to be humans, we found that mice lacking functional ABCA1 put on genetic variations of the known and potential interaction exhibit plasma lipid alterations that are concordant with those partners of this large molecule. observed in TD [27]. ABCA1 is localized on the plasma membrane and its surface More than 50 mutations within the coding region of the human expression is upregulated in macrophages by cholesterol ABCA1 gene have thus far been identified (for reference see The loading [27]. In the plasma membrane, ABCA1 is associated Human Gene Mutation Database, http://www.hgmd.cf.ac.uk). with a Lubrol-detergent resistant raft subfraction [33]. The fact W.E. Kaminski et al. / Biochimica et Biophysica Acta 1762 (2006) 510–524 513

Fig. 1. Phylogenetic consensus tree and chromosomal dispersion of human ABC A-subfamily transporter genes. Full length amino acid sequences were aligned using CLUSTALX (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. The chromosomal loci are schematically shown for each ABC A-subfamily transporter gene (arrowheads). Genomic mapping data for individual genes were updated by BLAT search (http://genome.ucsc.edu/) and may therefore, in some cases, slightly differ from previously proposed loci. Inset: Schematic representation of the structural organization of ABC A-transporters. Each family member is typically composed of two transmembrane domains (TMD1, TMD2), each containing six membrane-spanning α-helices (grey shaded barrels) and two nucleotide binding domains (NBD1, NBD2). Characteristic structural features also include a large extracellular loop between the first and second transmembrane helix (arrow) and two conserved 80-amino acid segments adjacent to the NBDs (asterisks). that ABCA1 is also detectable in the Golgi compartment and in occurs at a very low rate whereas nucleotide binding is lysosomes [27,34,35] supports the view that it is a mobile sufficient to induce conformational changes in this protein [38]. molecule that may shuttle between the plasma membrane, the This is in line with a more recent report which demonstrated that Golgi and the lysosomal compartment as constituent of a ATP is hydrolyzed at the nucleotide binding cassettes of vesicular transport route. Initial studies on the biologic role of ABCA1 also in mammalian HEK293 cells using vanadate- ABCA1 suggested it functions as a translocator of lipids induced nucleotide trapping [35,38]. The observed low ATP between the inner and outer plasma membrane [36]. This was turnover suggests that ABCA1 may rather act as a facilitator of based on experiments showing an increase in cholesterol and cholesterol/choline-phospholipid export within the cellular lipid phospholipid export under conditions of forced ABCA1 export machinery than exert a genuine translocator function. expression and in ABCA1 deficient cells which characteristi- However, this issue still needs to be addressed in more detail. cally display the reverse scenario [27]. Moreover, overexpres- The exact molecular mechanisms by which ABCA1 mediates sion experiments suggest that ABCA1 may actively mediate the export of lipid compounds from the cell are still unclear. In intracellular cholesterol transport [37]. Intriguingly, studies in this context, the question arises as to which molecular partners insect Sf9 cells indicated that the ATP turnover of ABCA1 interact with and thus potentially modulate ABCA1 function. 514 W.E. Kaminski et al. / Biochimica et Biophysica Acta 1762 (2006) 510–524

Table 3 leukocyte ABCA1 alone can exert significant anti-atheroscle- Human ABC transporter genes and associated monogenetic disorders rotic activity independently of plasma HDL levels. They also Gene Monogenetic disorder OMIM no. indicate that the absence of ABCA1 from only leukocytes is ABCA1 Tangier disease 205400 sufficient to induce aberrant monocyte recruitment into the Familial hypoapolipoproteinemia 604091 spleen identifying ABCA1 as a critical leukocyte factor in the ABCA3 Respiratory distress syndrome (Neonatal 267450 control of monocyte targeting [42]. The view that macrophage surfactant deficiency) ABCA1 functions as an important anti-atherosclerotic factor is ABCA4 Stargardt disease 248200 Retinitis pigmentosa 19 601718 supported by another study demonstrating that targeted Cone rod dystrophy 3 604116 inactivation of ABCA1 in macrophages leads to increased Age-related macular degeneration 153800 lesion formation and foam cell accumulation in apoE null ABCA12 Lamellar ichthyosis type 2 (Ichthyosis congenital IIB) 601277 mutant mice [43]. A reciprocal approach using ABCA1 Harlequin ichthyosis (Ichthyosis congenita, 242500 overexpressing transgenic apoE null mice revealed that forced Harlequin fetus type) ABCB4 Progressive familial intrahepatic cholestasis type 3 602347 expression of human ABCA1 results in the formation of ABCB7 X-linked sideroblastosis and anemia 301310 smaller, less-complex lesions in apoE knockout mice [44]. ABCB11 Progressive familial intrahepatic cholestasis type 2 601847 Collectively, these in vitro and in vivo findings underscore the ABCC2 Dubin–Johnson Syndrome 237500 critical role of ABCA1 in macrophage lipid homeostasis and ABCC6 Pseudoxanthoma elasticum 264800 highlight its significant anti-atherosclerotic activity. ABCC7 Cystic fibrosis (Mucoviscidosis) 219700 Congenital bilateral absence of the vas deferens 277180 Since the cloning of the ABCA1 promoter region, a number ABCC8 Familial persistent hyperinsulinemic 601820 of factors that control ABCA1 expression have been character- hypoglycemia of infancy ized. These include the transcription factor zinc finger protein ABCD1 Adrenoleukodystrophy 300100 ZNF202, which appears to function as a major repressor of β ABCG5 -sitosterolemia 210250 ABCA1 transcription [45], oncostatin M [46] and geranylger- ABCG8 β-sitosterolemia 210250 anyl pyrophosphate which directly acts as an antagonist of nuclear hormone receptor liver X receptor [47]. Importantly, the in vitro demonstration that the peroxisome proliferator activated For example, it has been shown that ABCA1 interacts with a β2- receptors PPARα and PPARγ activators induce ABCA1 syntrophin/utrophin complex that may couple ABCA1 to the F- expression in macrophage-derived foam cells suggests the actin cytoskeleton [39]. Moreover, ABCA1 function depends involvement of nuclear receptors in the activation of the on binding to Fas-associated death domain protein (FADD), an ABCA1 pathway in these cells [48,49]. This is supported by adaptor molecule involved in death receptor signal transduction experiments in chimeric LDLR−/− mice lacking PPARγ in their suggesting a potential interlink between ABCA1 and apoptosis hematopoietic cells which show a significant increase in [40]. atherosclerosis supporting the concept that PPARγ dependent Macrophages play a key role in the initiation and progression activation of macrophage ABCA1 expression is atheroprotec- of atherosclerotic lesions [41]. In the nascent lesion, they tive in vivo [49]. Next to PPARγ another nuclear receptor, liver transform into foam cells through the excessive accumulation of X receptor α, has also been implicated in sterol-dependent cholesteryl esters. Dysfunctional lipid homeostasis in macro- transactivation of the ABCA1 promoter [50,51]. Based on these phages and foam cells ultimately results in the breakdown of findings, promising efforts have been initiated to identify drugs membrane integrity and cell death. The findings that ABCA1 is targeting the PPARγ – liver X receptor – ABCA1 regulatory upregulated in human macrophages during sustained uptake of circuit which can be used to therapeutically influence the cholesterol [18,27] and that it facilitates cholesterol export from progression of atherosclerosis [52]. In this context, the recent the cell early on suggested its implication in foam cell demonstration in LDLR−/− mice that atheroprotection mediat- development and the formation of lesions of atherosclerosis. ed by PPARγ can also occur independently of ABCA1 suggests Among patients with defective ABCA1 one subgroup that this receptor may exert its antiatherosclerotic effect through develops premature atherosclerosis, whereas another one more than one pathway [53]. presents predominantly with splenomegaly [26] indicating Besides these well-established regulatory factors, available differences in macrophage targeting to tissues in ABCA1 evidence suggests critical roles for unsaturated fatty acids in the deficiency. Recent experiments using chimeric LDLR−/− mice control of ABCA1 activity. This is based on the observation that lacking ABCA1 in their circulating cells demonstrate that the unsaturated but not saturated fatty acids markedly inhibit selective disruption of ABCA1 in circulating cells, in ABCA1 dependent cholesterol/phospholipid efflux from particular macrophages, impacts macrophage targeting into macrophages [54]. Recent studies suggest that this effect is the vascular wall and lesion formation in vivo. LDLR−/− likely the result of reduced ABCA1 gene expression [55] and chimeras deficient in ABCA1 develop significantly larger increased ABCA1 degradation [54]. The latter mechanism (60%) and more advanced atherosclerotic lesions compared to appears to involve stearoyl-CoA desaturases and the PLD2 chimeric LDLR−/− mice with functional ABCA1 in hemato- signaling pathway [56,57]. Because unsaturated fatty acids are poietic cells [42]. Importantly, targeted disruption of leukocyte typically elevated in diabetes, increased levels of nonsaturated ABCA1 function in this study did not affect plasma HDL lipids may significantly contribute to low HDL cholesterol in cholesterol levels. These results provide direct evidence that patients with diabetes. Such a pathophysiological scenario W.E. Kaminski et al. / Biochimica et Biophysica Acta 1762 (2006) 510–524 515 might define an important mechanistic interlink between acid residues [64]. The demonstration that defects in the ABCA3 cholesterol metabolism and diabetes. gene cause neonatal surfactant deficiency identifies this transporter as a critical regulator of lung surfactant metabolism. 3.2. ABCA3 and neonatal surfactant deficiency The detailed molecular mechanisms by which ABCA3 exerts its function in pneumocytes are presently unknown. A potential After the initial discovery of ABCA1 and ABCA2, a third clue comes from the observation that patients with mutated homologous protein, designated ABCA3, was discovered in ABCA3 showed abnormal lamellar bodies in their lung tissue. 1996 from a human medullary thyroid carcinoma cell line The lamellar bodies in these infants are small and tightly packed [58,59]. ABCA3 encodes a 1704 amino acid protein of 190 kDa with eccentrically positioned densely stained inclusions. size (Table 1) [60]. The ABCA3 gene is located on chromosome Mechanistically, it is thus likely that ABCA3 is directly 16p13.3 in close proximity to the human homolog of the rodent implicated in phospholipid translocation processes that are testis specific ABC transporter, AbcA17 (A. Piehler, unpub- critical for the proper formation of lamellar bodies and the lished). ABCA3 shows highest expression in the lung but is also subsequent secretion of surfactant into alveoli. expressed in brain, heart and pancreas. Ultrastructural studies Of note, not all individuals with mutations in the ABCA3 revealed that in the lung ABCA3 is expressed exclusively on the gene in this study died from respiratory failure suggesting that limiting membranes of so-called lamellar bodies of alveolar mutations in this transporter are also associated with milder type II pneumocytes [60]. forms of pediatric interstitial lung disease. To test this Pulmonary surfactant is a mixture of lipids, mostly possibility, ABCA3 mutation analysis was performed in a phospholipids, and proteins that is essential for normal cohort of children with chronic lung disease of unknown breathing. It forms a lipid-rich monolayer that coats the airways etiology [66]. Intriguingly, in three out of four patients with the of the lung and lowers surface tension at the air–liquid interface histological diagnosis of desquamative interstitial peumonitis, thus preventing end-expiratory collapse of the alveoli. The who were older than 10 years at the time of enrollment, lipids and proteins that make up surfactant are assembled in heterozygosity for a novel missense mutation (E292V) was lamellar bodies from which they are secreted into the alveolar found. Heterozygosity for the E292V mutation was detected in space [61]. Selective expression of ABCA3 in lamellar bodies seven additional patients and in eight of the ten patients a early on pointed to its potential implication in surfactant second, distinct mutation was identified on the other ABCA3 metabolism, a hypothesis that was supported by several other allele. These findings document that genetic variants in the observations. In the rat, ABCA3 mRNA expression is strongly ABCA3 gene not only cause a neonatal phenotype associated induced during lung development and highest ABCA3 mRNA with severe surfactant deficiency but may also control levels are found shortly before birth synchronously with the susceptibility to milder forms of interstitial lung disease. transcriptional induction of the surfactant-associated proteins. Further, in vitro incubation of human fetal lung explants with 3.3. ABCA4 (ABCR) and retinal dystrophies dexamethasone results in a dramatic increase in ABCA3 mRNA expression relative to controls [62]. This regulatory response ABCA4 (also known as ABCR or the rim protein) is a could also be observed on the protein level in rats [63]. The retinal-specific member of the family of ABC transporters. It ABCA3 promoter contains a functional glucocorticoid-respon- was the first ABC A-transporter that has been causatively sive element (GRE) as evidenced by the findings that linked to genetic disease [21,22]. It encodes a 2273 amino transcriptional activity mediated by the GRE containing region acid full-size ABC transporter protein which is localized in the shows a twofold increase in the human alveolar type II cell line retina along the rims and incisures of rod and cone A549 in response to dexamethasone and specific binding of the photoreceptor outer segment disk membranes [21,22,67,68]. glucocorticoid receptor to the GRE could be demonstrated [63]. Available evidence suggests that ABCA4 may act as an ATP Based on these data, strongly suggesting roles for ABCA3 in dependent flippase that translocates N-retinylidene-phosphati- surfactant metabolism, Shulenin and colleagues [64] screened dylethanolamine (-PE) from the lumen to the cytoplasmic side 21 ethnically diverse full-term newborns with fatal surfactant of the disk membrane. This action promotes the recycling of deficiency for mutations in the ABCA3 gene. In these subjects all–trans retinal released from photobleached rhodopsin via no known causes for the respiratory distress syndrome including the retinoid cycle. It has thus been suggested that compro- mutations in the surfactant protein B or C could be found. mised ABCA4 transporter activity may lead to the accumu- Clinically, the onset of respiratory symptoms had occurred lation of toxic all–trans retinal derivatives in rods and cones, shortly after birth and the majority of these infants died within a which results in apoptosis of the supporting retinal pigment month after birth. Histological sections of the lung showed the epithelium cells and, ultimately, degeneration of the photo- picture of desquamative interstitial pneumonitis and/or pulmo- receptors [69–71]. This view is in agreement with the recent nary alveolar proteinosis. A similar phenotype can be observed observation that ABCA4 indeed binds the retinoid N-retinyli- in patients with mutations in the surfactant protein B [65].In16 dene-PE with high affinity [72]. To date >400 sequence of the 21 infants, mutations in the ABCA3 gene were found. variations in the ABCA4 gene have been documented (for a Genetic abnormalities include homozygous nonsense and current synopsis see http://www.retina-international.org/sci- frameshift mutations, heterozygous insertions and splice-site news/abcrmut.htm) and linked to four degenerative retinal mutations, and also missense mutations in conserved amino diseases including Stargardt disease (STGD), cone-rod 516 W.E. Kaminski et al. / Biochimica et Biophysica Acta 1762 (2006) 510–524 dystrophy type 3 (CRD3), retinitis pigmentosa type 19 (RP19) AMD [84,87]. The controversial findings in the context of and age-related macular degeneration (AMD), respectively. AMD highlight the specific problems in the evaluation of the STGD is an autosomal recessive macular dystrophy causing pathogenetic relevance of mutations in large genes such as the progressive impairment of central vision, which clinically transporter ABCA4. It also emphasizes the need to take manifests typically in childhood or young adulthood. Affected environmental and additional hereditary factors into account individuals display atrophic lesions in the macula, as well as in the interpretation of mutation data sets associated with characteristic yellowish flecks in the macular and perimacular ABCA4. Bearing in mind the fact that 7% of individuals age >75 region [73]. Allikmets et al. (1997) provided the first report years are affected with late-stage AMD [90] and an estimated demonstrating that patients with STGD have mutations in their mutant ABCA4-heterozygote frequency of 2–3% in the general ABCA4 gene [22]. Subsequent extensive mutation analyses population [22], in detail characterization of the pathogenetic have confirmed that ABCA4 is the gene underlying STGD and role of ABCA4 in AMD will be a major challenge for the future. have initiated a characterization of the mutational spectrum [74–79]. Interestingly, some mutant alleles such as G863A, 3.4. Defective ABCA12 causes two congenital keratinization A1038V, and G1961E, respectively, appear to be more common disorders and may have altered frequencies in different populations, presumably as a result of a founder effect [76,80]. ABCA12 was recently discovered in human placenta [91]. Previous analyses of ABCA4 mutations in individuals with Four full-length cDNAs were identified that contain two STGD, AMD, CRD3, or RP19 led to the suggestion of a model different polyadenylation sites and two splice variants coding in which ABCA4 mutations can cause a spectrum of retinal for two distinct ABCA12 isoforms of 2595 and 2516 aa size, disease, with the clinical phenotype determined by the level of respectively [91]. ABCA12 shares significant amino acid residual ABCA4 protein activity (residual activity model) sequence homology with ABCA1 (36%), ABCA7 (36%) and [74,76,81,82]. For example, the homozygous frameshift ABCA3 (35%). RT-PCR experiments revealed highest expres- mutation 5917delG is associated with a relatively severe sion levels in skin, testis and fetal brain [91]. The gene is STGD phenotype and the truncating mutations Y362X and composed of 53 exons and maps to chromosome 2q34, a region R1300X, respectively, are associated with milder clinical that harbors, among others, a locus for the keratinization symptoms [77,81]. Although, no direct assay for the assessment disorder lamellar ichthyosis [92] identifying ABCA12 is a of the transporter activity of ABCA4 is currently available, this positional candidate for this hereditary skin disease. concept is supported by a series of indirect observations Indeed, Lefevre et al. [93] found missense mutations in the including human genetics studies that correlate age of onset ABCA12 gene in nine African families with lamellar and/or phenotypes conveyed by the selective combination of ichthyosis type 2, an autosomal recessive form of ichthyosis mutant ABCA4 alleles [75,83]. Moreover, studies in Abca4 which is characterized by skin desquamation over the whole knockouts, which demonstrate that these null mutant mice body with large, adherent, pigmented and dark scales. The partially develop human retinal disease by manifesting the mutations were homozygous in 8 consanguineous families accumulation of lipofuscin, delayed dark adaptation and slow and heterozygous in one non-consanguineous family. Four of progression of photoreceptor degeneration support the recipro- the missense mutations were located in the highly conserved cal correlation between ABCA4 activity and clinical phenotype first ATP-binding cassette, which is essential for the integrity [70,71,84,85]. Autosomal recessive retinitis pigmentosa 19 is of ABC transporter function. Two recent independent studies the most severe retinal dystrophy caused by mutations in the demonstrated that mutations in the ABCA12 gene also ABCA4 gene and is believed to be caused by complete loss of underlie another keratinization disorder-harlequin ichthyosis ABCA4 activity. Consistent with the residual activity model [94,95]. The majority of the patients suffering from this truncating or aberrant splicing mutations are predominantly disease was homozygous or compound heterozygous for found in families with RP19 [81,82,86]. mutations (deletions, insertions or splice junction mutations) AMD accounts for more than half of severe visual that completely altered the amino acid sequence of the protein impairment in studied populations of European descent, with or resulted in the deletion of amino acid residues in highly at least 1.7 million individuals affected in the USA [87]. conserved domains suggesting a complete disruption of the According to the residual activity model, the mild end of the protein function. These findings indicate that the nature and ABCA4 associated phenotypic spectrum would be AMD, severity of mutations in the ABCA12 gene account for two resulting from either homozygosity for a very mild mutation or clinical phenotypes: a severe one presenting as harlequin heterozygosity for a moderate or severe alteration. Initially, an ichthyosis and a milder form manifesting as lamellar association between AMD and heterozygous mutations in ichthyosis type 2. ABCA4 has indeed been established [22]. This was supported Harlequin ichthyosis is the most severe form of congenital by the observation that the frequency of two common ABCA4 ichthyosis [96,97]. It is characterized by a profound variants, G1961E and D2177N, in 1200 patients with AMD is thickening of the keratin layer in fetal skin. Affected neonates significantly higher (3.4%) than that of controls (0.95%) [88]. are born with a massive horny shell of dense platelike scale However, other studies could not confirm these results [77,89]. and contraction abnormalities of the eyes, the ears, the mouth, More recent reports in both humans and mice suggest that and the appendages. This “armor” limits movement and ABCA4 is a dominant susceptibility locus for predisposition to compromises the protective skin barrier leading to excessive W.E. Kaminski et al. / Biochimica et Biophysica Acta 1762 (2006) 510–524 517 water loss, electrolyte abnormalities, temperature dysregula- also underlie hereditary disorders. This group of potential tion, and increased risk of life-threatening infection. Affected candidate genes includes ABCA2, the ABCA6-like cluster babies mostly die within a few days after birth because of (ABCA5, ABCA8, ABCA9, ABCA10) and ABCA13, respectively. feeding complications, respiratory distress and severe infec- tions. The term harlequin derives from the newborn's facial 4.1. ABCA2 expression and the triangular and diamond-shaped pattern of hyperkeratosis. ABCA2 was originally co-identified with ABCA1 in mice During normal keratinocyte differentiation, lipids accumu- [10]. The human gene was cloned in 2001 by our laboratory [99] late in so-called lamellar granules (LG) which are subsequent- and also by another group [100]. The ABCA2 full-length cDNA ly extruded into the intercellular spaces where they undergo is 7.3 kb in size and codes for a 2436 amino acid polypeptide enzymatic processing to produce a lipid mixture consisting of with a calculated molecular weight of ∼270 kDa (Table 1). ceramides, cholesterol and fatty acids [98]. This lipid complex Genomic analysis identified a total of 48 exons extending across fills most of the intercellular space of the stratum corneum a genomic region of only 21 kb on chromosome 9q34 [99]. The forming the water permeability barrier of the skin. Immuno- majority of introns are less than 0.3 kb in size which accounts for histochemistry demonstrated that ABCA12 is present in the the unusually compact genomic organization. Recently, an upper epidermal layers of normal human skin and immunoe- additional 5′ exon was identified encoding an alternative unique lectron microscopic localization studies revealed its exclusive N-terminus with highest expression in lysosomal compartments presence in LG of normal epidermal keratinocytes [95].LG of peripheral blood leukocytes [101]. Amino acid sequence are specialized lipid-rich organelles characteristically found in homology analysis places ABCA2 into the same evolutionary epidermal granular cells. ABCA12 containing LG were subgroup as ABCA1, ABCA3, ABCA4 and ABCA7, respec- abundantly detected close to the cell membrane where they tively (Fig. 1). Expression profiling showed highest levels of fused with the cell membrane to secrete their lipid content to ABCA2 mRNA levels in the brain, however, expression was the extracellular space of the stratum corneum. These also detected in a broad range of tissues including monocytes, observations clearly show expression of ABCA12 in kerati- macrophages, kidney, liver, thymus, heart, ovary, lung and nocytes during keratinization and they suggest its implication various tumor cells [10,99–103]. Using a semiquantitative RT- in the LG dependent lipid export pathway. The lipid PCR approach, we demonstrated sterol-sensitive regulation of compounds whose translocation is mediated by ABCA12 are the ABCA2 gene in human macrophages suggesting a role for unknown. Ultrastructurally, harlequin ichthyosis is character- this transporter in monocyte/macrophage lipid metabolism [99]. ized by abnormal or absent lamellar granules [96] indicating Analysis of the putative ABCA2 promoter region revealed that the assembly of these lipid-rich organelles is perturbed in several potential binding sites for transcription factors with the absence of functional ABCA12. Furthermore, cultured functions in myeloid and neural cell differentiation and keratinocytes of harlequin ichthyosis patients exhibit a activation [104]. Luciferase reporter gene experiments showed congested pattern of glucosylcermide, a major lipid compo- the importance of two GC-rich regions and overlapping binding nent of LG, around the nuclei compared to healthy sites for the EGR-1 and Sp1 transcription factors in the control of keratinocytes. Corrective ABCA12 gene transfer into ABCA2 gene expression [105]. ABCA12 deficient keratinocytes increased the number of Although the ABCA2 gene has been described almost a keratinocytes showing the diffuse glucoceramide staining decade ago, little is known about its function. Overexpression of present in healthy keratinocytes [95]. These data together a GFP-tagged ABCA2 chimeric protein revealed that ABCA2 with the known colocalization of ABCA12 and LG strongly localizes to the endolysosomal compartment and the Golgi suggest that ABCA12 is implicated in intracellular transloca- apparatus [100] which is consistent with another study tion processes of sphingolipids that are required for maintain- demonstrating the presence of ABCA2 in the endolysosomal ing the integrity of lamellar granules. compartment of rat oligodendrocytes [103]. Two studies which It should be pointed out that the A-subclass transporters report resistance of ABCA2 overexpressing HEK293 cells to ABCA12 and ABCA3 have in common that they are exclusively the estrogen-based antitumor drug estramustine and an localized in a secretory intracellular lipid storage compartment, association of increased ABCA2 expression with resistance to i.e., lamellar granules in keratinocytes and lamellar bodies in the chemotherapeutic agent mitoxantrone in a small cell lung pneumocytes, respectively [60,95]. It is thus tempting to cancer cell line suggest the implication of ABCA2 in multidrug speculate that both transporters evolved from the same resistance [100,106]. At this point, the clinical implications of primordial lipid export system during the development of the these findings remain unclear. Given its localization in the respiratory system and the integument at the time when lysosome, ABCA2 may facilitate the transport of cytotoxic vertebrates left the aquatic environment. compounds from the cytoplasm to the lysosomal compartment for detoxification. It needs to be cautioned, however, that the 4. Potential disease causing ABC A-subfamily members extrusion of xenobiotics, a common feature of many ABC transporters, is not necessarily related to the bona fide Given the association of the ABC A-transporters ABCA1, physiological function of ABCA2. ABCA3, ABCA4 and ABCA12 with genetic diseases, it is Taken together, the high expression levels in the brain, the almost predictable that other members of this subfamily may localization in oligodendrocytes and sterol-sensitive regulation 518 W.E. Kaminski et al. / Biochimica et Biophysica Acta 1762 (2006) 510–524 suggest functions for ABCA2 in neural transmembrane lipid quantitative expression profiles. Typically, at least one alterna- transport. In line with this view, transfection experiments tive mRNA variant exists for each ABCA6-like transporter demonstrate that ABCA2 expression levels influence the mostly coding for truncated hypothetical protein products expression of a number of genes linked to Alzheimer's disease (Table 1) [11,109,111,112]. (AD) including amyloid β precursor protein (chromosome The biological significance of ABCA6-like transporters is 21q21.3) whose pathogenetic role in AD is well established unclear. The finding that the genes for ABCA6, ABCA9 and [107]. Other authors noted an association between early onset ABCA10 are regulated by cholesterol in human macrophages AD and the synonymous SNP rs908832 in exon 14 of the points to their potential involvement in lipid transport processes ABCA2 coding region [108]. However, more extensive studies in these cells. Of importance may be the fact that these are required to corroborate such an association, in particular ABCA6-like transporters display regulatory profiles that are because the ABCA2 polypeptide structure is not affected by the consistently reciprocal to those of ABCA1, ABCA2, and silent C/T variant. More importantly, several hereditary ABCA7, respectively [11,109,112] raising the possibility that neurological disorders have been linked to the ABCA2 locus both transporter groups may (in part) exert antagonistic on chromosome 9q34 including amyotrophic lateral sclerosis 4 functions in macrophages. An important clue to possible in (OMIM 602433), the lethal congenital contraction syndrome vivo functions of ABCA6-like transporters comes from most (OMIM 253310), autosomal recessive deafness 33 (OMIM recent murine experiments demonstrating that ABCA5 is 607239) and Joubert syndrome, a pathology associated with localized in the endolysosomal compartment and Abca5 hypoplasia of the cerebellar vermis (OMIM 213300). ABCA2 is deficient mice develop a dilated heart reminiscent of dilatative thus a promising positional candidate gene for these neurolog- cardiomyopathy leading to fatal cardiac failure [113]. Abca5 ical diseases. knockouts also exhibit exophthalmos and a collapse of the thyroid gland. Collectively, the observed abnormalities in 4.2. ABCA6-like transporters cardiomyocytes and follicular cells are consistent with the view that Abca5 may serve critical functions in the endolysosomal Five closely related members of the human ABC A- system. It will be fascinating to investigate whether mutations subfamily form a compact gene cluster on chromosome in the ABCA5 gene cause an equivalent of this murine 17q24.2–3 comprising the genes for ABCA5, ABCA10, phenotype that exists in human pathology. ABCA6, ABCA9 and ABCA8 (in that order). This genomic organization is unique among human ABC transporters. Their 4.3. ABCA7 common chromosomal location of the ABCA6-like transpor- ters and their strikingly high overall peptide sequence The A-subfamily transporter ABCA7 was initially cloned identities, ranging from 42 to 72% (Fig. 1, Table 2), strongly from human macrophages in which it is subject to regulation support the hypothesis that these transporters evolved from a by cholesterol influx and efflux [20]. The ABCA7 cDNA is of common ancestral gene [1,11]. Because the human ABCA6 6.8 kb size encoding a polypeptide of 2146 amino acids with a gene was the first to be characterized in completeness [109], calculated molecular weight of 220 kDa which exhibits the members of the ABC A-transporter pentacluster have been highest protein sequence homology with ABCA1 (54%) and referred to as “ABCA6-like transporters” [11].Withthe ABCR (49%) [20,114]. ABCA7 is predominantly expressed in exception of ABCA10, all ABCA6-like transporters are myelo-lymphatic tissues with highest expression in peripheral found in the rodent genome suggesting that the initial leukocytes, thymus, spleen, and bone marrow, but also in duplication events have taken place before the divergence of platelets and keratinocytes [20,115,116]. The ABCA7 gene the rodent and primate lineages. Phylogenetic analysis suggests consists of 46 small exons which are separated by relatively that ABCA5 is the oldest gene in the ABCA6-like transporter small intron sequences [117] and several alternative mRNA gene cluster and the other members are the result of a cascade variants have been identified (W. Kaminski, unpublished). The of duplication events (see Fig. 1). The recent observation that molecular function of ABCA7 is a currently unresolved issue. the Fugu rubripes genome has only one ortholog of the cluster Overexpression experiments in human HeLa and HEK293 (ABCA5) supports this view and chronologically positions the cells suggest that ABCA7 is implicated in the regulation of expansion of the ABCA6-like transporter genes after the split ceramide and phospholipid export from the cell but not of of the teleost lineage [12]. cholesterol [115,118], whereas other data demonstrate in- Historically, ABCA8 was the first human ABCA6-like creased efflux of both cholesterol and phospholipids in transporter to be cloned [110], followed by ABCA6, ABCA9, ABCA7 transfected HEK293 cells [119]. Current data on the ABCA5 and ABCA10, respectively, which were identified by our subcellular localization of ABCA7 are also confusing. Initial laboratory and others during the past years [11,109,111,112]. experiments in ABCA7 overexpressing HEK293 cells indi- The defining member ABCA6, a polypeptide of 1617 amino cated its presence in the plasma membrane [118] which acids, bears the structural features of full-size transporters, contrasts with the recent finding, by the same group, that however, like all other ABCA6-like transporters, it is ABCA7 is predominantly localized intracellularly but not at significantly smaller in size than ABC A-transporters outside the plasma membrane in mouse peritoneal macrophages [120]. this subgroup (Table 1). ABCA6-like transporters generally The situation is complicated by studies in Abca7 null mice show a broad tissue-specific distribution with individual whose macrophages were found to have normal cholesterol W.E. Kaminski et al. / Biochimica et Biophysica Acta 1762 (2006) 510–524 519 and phospholipid efflux rates [121] precluding an indispens- among all human ABC A-transporters in that the N-terminal able function of Abca7 in the cholesterol/phospholipid export extracellular loop consists of more than 3500 aa. This in the mouse. Intriguingly, the Abca7 knockout approach hydrophilic domain is conserved in the mouse, but no revealed a gender dependent reduction in visceral fat and significant homology to any other protein domain could be serum cholesterol levels. It remains to be established whether identified so far. ABCA13 displays highest amino acid these unexpected observations are a species-specific physio- sequence identity with ABCA12 (38%), ABCA1 (36%) and logical characteristic of mice or whether they represent ABCA7 (36%), respectively (Table 2). In normal tissues, important clues to as yet unsuspected roles of ABCA7 in highest mRNA expression of the ABCA13 full-length mRNA human lipid metabolism. was found in human trachea, testis and bone marrow. Interestingly, the ABCA7 gene is intimately physically Expression profiling in tumor cell lines showed highest linked to the gene for the minor histocompatibility antigen mRNA levels in leukemia, brain and prostate tumor cell lines, HA-1 on chromosome 19p13.3. Both genes are arranged in respectively [125]. Presently, little is known about the role of a head-to-tail array with only 1.7 kb distance between the ABCA13 in physiology and disease. ABCA13 shares a common terminal exon of ABCA7 and the initial exon of the HA-1 genomic region on chromosome 7p12.3 with the locus linked to gene [117]. It thus cannot be entirely ruled out that the the T-cell tumor invasion and metastasis, INM7 [125]. ABCA7 and HA-1 genes overlap raising the possibility that a Interestingly, several potential binding sites for transcription functional and regulatory interlink exists between both factors associated with hematopoiesis of the myeloid and genes. HA-1 is a cytosolic protein of 1165 amino acid lymphoid lineages have been identified in the murine ABCA13 size [110] and unknown function. An H168R polymorphism promoter [126]. Together, these results and the high expression in the HA-1 polypeptide sequence has been identified as the levels in leukemic cell lines, render ABCA13 a possible immunologic target for HA-1 specific cytotoxic T cells candidate player in hemato-oncological pathologies. [122]. Available information suggests that ABCA7/HA-1 may be involved in autoimmune disease. On the one hand, 5. Conclusions this is based on the fact that both genes are expressed in macrophages and lymphocytes, major effector cells in Significant evidence has accumulated during the past years chronic inflammation. On the other hand, database search to support the concept that ABC A-subfamily transporters serve in our laboratory revealed that a polypeptide of app. 150 critical functions in human physiology which, when they are amino acids length within the first extracellular domain of defective, cause disease. Currently, available data allow us to ABCA7 is recognized by antisera from Sjögren's syndrome begin to outline what may be characteristic features of these patients (“Sjögren epitope”) suggesting that ABCA7 is transporter molecules. One of the emerging key features is that associated with the pathogenesis of this autoimmune disease. they appear to function as complex and highly specialized A recent study demonstrated no association between allelic transport platforms that mediate the translocation of physiologic variants of the ABCA7 gene and Sjögren's syndrome, lipid compounds across biological membranes. Known or however, it revealed that the 168H variant of the minor potential substrates of ABC A-transporters include phospholi- histocompatibility antigen HA-1 is associated with reduced pids (ABCA1, ABCA3, ABCA4, ABCA7), cholesterol risk of primary Sjögren's syndrome [123]. That these results (ABCA1) and sphingolipids (ABCA12). As with other human do not entirely exclude the potential involvement of ABCA7 ABC proteins, we still await clarification on how ABC A- in Sjögren's syndrome is evidenced by recent work subclass transporters mediate the translocation of their specific reporting that ABCA7 is expressed in salivary glands of substrates on a molecular level. This task is complicated by a patients with Sjögren's syndrome [124]. Further efforts are growing body of evidence suggesting that ABC transporters do required to assess the role of the ABCA7/HA-1 gene not act alone but rather function as components of molecular complex in Sjögren's syndrome and also in other autoim- multi-unit complexes. In the case of ABCA1, such a mune disorders. translocator complex, which controls the cellular export of cholesterol and phospholipids, may include β1-andβ2- 4.4. ABCA13 syntrophin, utrophin and phospholipid transfer protein as its molecular constituents [39,40,127,128]. ABCA13 is by far the largest ABC transporter with a The most important lesson that we have thus far learned molecular mass of app. 576 kDa [125]. The full-length about human ABC A-transporters comes from mutation transcript cloned from lung RNA comprises 17209 bp with an analyses. The still limited number of studies revealed a open reading frame of 15195 bp and five additional alterna- broad spectrum of both mutations and clinical phenotypes for tively spliced mRNA variants have been identified presumably each ABC A-protein that has been causatively linked to encoding truncated isoforms of the canonical ABCA13 protein disease. This pleiotropism has been documented most [125]. Interestingly, the cDNA of three transcript variants convincingly for the transporter ABCA4 (ABCR), for which contain a second open reading frame at the 5′ end coding for an more than 400 mutations have been reported to date which, unrelated hypothetical protein of 717 aa size. The human altogether, give rise to a wide range of clinical manifestations. ABCA13 gene is located on chromosome 7p12.3 and consists of Future studies will help to determine whether a similar extent 62 exons. The predicted ABCA13 polypeptide stands out of genotype/phenotype diversity also exists for other ABC A- 520 W.E. Kaminski et al. / Biochimica et Biophysica Acta 1762 (2006) 510–524 transporters. In particular, this holds true for the recently [10] M.F. Luciani, F. Denizot, S. Savary, M.G. Mattei, G. Chimini, Cloning of discovered disease-causing genes, ABCA3 and ABCA12, two novel ABC transporters mapping on human chromosome 9, Genomics 21 (1994) 150–159. which have not yet received the same longstanding scientific [11] A. Piehler, W.E. Kaminski, J.J. Wenzel, T. Langmann, G. Schmitz, attention as ABCA4. 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