|ATP-binding cassette, sub-family A (ABC1), member 4|
|RNA expression pattern|
ABCA4 is a member of the ATP-binding cassette transporter gene sub-family A (ABC1) found exclusively in multicellular eukaryotes. The gene was first cloned and characterized in 1997 as a gene that causes Stargardt disease, an autosomal recessive disease that causes macular degeneration. The ABCA4 gene transcribes a large retina-specific protein with two transmembrane domains (TMD), two glycosylated extracellular domains (ECD), and two nucleotide-binding domains (NBD). The ABCA4 protein is almost exclusively expressed in retina localizing in outer segment disk edges of rod photoreceptors.
Previously known as the photoreceptor rim protein RmP or ABCR, the recently proposed ABCA4 structure consists of two transmembrane domains (TMDs), two large glycosylated extracellular domains (ECD), and two internal nucleotide binding domains (NBDs). One TMD spans across membranes with six units of protein linked together to form a domain. The TMDs are usually not conserved across genomes due to its specificity and diversity in function as channels or ligand-binding controllers. However, NBDs are highly conserved across different genomes—an observation consistent with which it binds and hydrolyzes ATP. NBD binds adenosine triphosphate molecules (ATP) to utilize the high-energy inorganic phosphate to carry out change in conformation of the ABC transporter. Transcribed ABCA4 forms into a heterodimer: the two dimerized compartments of the channel are different from each other. When TMDs are situated in a membrane, they form a barrel-like structure permeable to retinoid ligands and control channel access to its binding sites. Once an ATP is hydrolized at the NBDs of the channel, NBDs are brought together to tilt and modify TMDs to modulate ligand binding to the channel. A recently proposed model of retinoid transfer occurring as a result of alternating exposure of external and internal TMD ligand binding sites, all controlled by binding of ATP, is based on recent structural analyses of bacterial ABC transporters.
ABCR is localized to outer segment disk edges of rods and cones. ABCR is expressed much less than rhodopsin, approximately at 1:120. Comparisons between mammalian ABCA4 to other ABCs, cellular localization of ABCA4, and analyses of ABCA4 knockout mice suggest that ABCA4 may function as an inward-directed retinoid flippase. Flippase is a transmembrane protein that "flips" its conformation to transport materials across a membrane. In the case of ABCA4, the flippase facilitates transfer of N-retinyl-phosphatidylethanolamine (NR-PE), a covalent adduct of all-trans retinaldehyde (ATR) with phosphatidylethanolamine (PE), trapped inside the disk as charged species out to the cytoplasmic surface. Once transported, ATR is reduced to vitamin A and then transferred to retinal pigment epithelium to be recycled into 11-cis-retinal. This alternating access-release model for ABCA4 has four steps: (1) binding of ATP to an NBD to bring two NBDs together and expose outer vestibule high affinity binding site located in TMD, (2) binding of NR-PE/ATR on extracellular side of the channel, (3) ATP hydrolysis promoting gate opening and movement of NR-PE/ATR across the membrane to the low-affinity binding site on the intracellular portion of TMD, and (4) release of adenosine diphosphate (ADP) and inorganic phosphate (Pi) to release the bound ligand. The channel is then ready to transfer another molecule of NR-PE/ATR again.
The ABCR -/- knockout mouse has delayed dark adaptation but normal final rod threshold relative to controls. This suggests bulk transmembrane diffusion pathways that remove ATR/NR-PE from extracellular membranes. After bleaching the retina with strong light, ATR/NR-PE accumulates significantly in outer segments. This accumulation leads to formation of toxic cationic bis-pyridinium salt, N-retinylidene-N-retinyl-ethanolamine (A2E), which causes human dry and wet age-related macular degeneration. From this experiment, it was concluded that ABCR has a significant role in clearing accumulation of ATR/NR-PE to prevent formation of A2E in extracellular photoreceptor surfaces during bleach recovery.
Mutations in ABCA4 gene are known to cause the autosomal-recessive disease Stargardt macular dystrophy (STGD), which is a hereditary juvenile macular degeneration disease causing progressive loss of photoreceptor cells. STGD is characterized by reduced visual acuity and color vision, loss of peripheral vision, delayed dark adaptation, and accumulation of autoflourescent RPE lipofuscin. Removal of NR-PE/ATR appears to be significant in normal bleach recovery and to mitigate persistent opsin signaling that causes photoreceptors to degenerate. ABCA4 also mitigates long-term effects of accumulation of ATR that results in irreversible ATR binding to a second molecule of ATR and NR-PE to form dihydro-N-retinylidene-N-retinyl-phosphatidyl-ethanolamine (A2PE-H2). A2PE-H2 traps ATR and accumulates in outer segments to further oxidize into N-retinylidene-N-retinyl-phosphatidyl-ethanolamine (A2PE). After diurnal disk-shedding and phagocytosis of outer segment by RPE cells, A2PE is hydrolyzed inside the RPE phagolysosome to form A2E. Accumulation of A2E causes toxicity at the primary RPE level and secondary photoreceptor destruction in macular degenerations.
The GENEVA Cleft Consortium study first identified ABCA4 as being associated with cleft lip and/or cleft palate with multiple markers giving evidence of linkage and association at the genome-wide significance level. Although SNPs in this gene are associated with cleft lip/palate there is no functional or expression data to support it as the etiologic gene which may, instead, lie in a region adjacent to ABCA4. A combination of genome wide association, rare coding sequence variants, craniofacial specific expression, and interactions with IRF6 support a role for the adjacent ARHGAP29 gene to be the likely etiologic gene playing a role in nonsyndromic cleft lip and/or palate.
- "Entrez Gene: ABCA4 ATP-binding cassette, sub-family A (ABC1), member 4".
- Allikmets R, Singh N, Sun H, Shroyer NF, Hutchinson A, Chidambaram A, Gerrard B, Baird L, Stauffer D, Peiffer A, Rattner A, Smallwood P, Li Y, Anderson KL, Lewis RA, Nathans J, Leppert M, Dean M, Lupski JR (March 1997). "A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy". Nature Genetics 15 (3): 236–46. doi:10.1038/ng0397-236. PMID 9054934.
- Nasonkin I, Illing M, Koehler MR, Schmid M, Molday RS, Weber BH (January 1998). "Mapping of the rod photoreceptor ABC transporter (ABCR) to 1p21-p22.1 and identification of novel mutations in Stargardt's disease". Human Genetics 102 (1): 21–6. doi:10.1007/s004390050649. PMID 9490294.
- Allikmets R, Shroyer NF, Singh N, Seddon JM, Lewis RA, Bernstein PS, Peiffer A, Zabriskie NA, Li Y, Hutchinson A, Dean M, Lupski JR, Leppert M (September 1997). "Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration". Science 277 (5333): 1805–7. doi:10.1126/science.277.5333.1805. PMID 9295268.
- Sun H, Nathans J (2000).  ABCR: Rod photoreceptor-specific ABC transporter responsible for Stargardt disease. "ABCR: rod photoreceptor-specific ABC transporter responsible for Stargardt disease". Methods in Enzymology. Methods in Enzymology 315: 879–97. doi:10.1016/S0076-6879(00)15888-4. ISBN 978-0-12-182216-3. PMID 10736747.
- van Meer G, Halter D, Sprong H, Somerharju P, Egmond MR (February 2006). "ABC lipid transporters: extruders, flippases, or flopless activators?". FEBS Letters 580 (4): 1171–7. doi:10.1016/j.febslet.2005.12.019. PMID 16376334.
- Sullivan JM (March 2009). "Focus on Molecules: ABCA4 (ABCR) - An import-directed photoreceptor retinoid flipase". Experimental Eye Research 89 (5): 602–3. doi:10.1016/j.exer.2009.03.005. PMID 19306869.
- Weng J, Mata NL, Azarian SM, Tzekov RT, Birch DG, Travis GH (July 1999). "Insights into the function of Rim protein in photoreceptors and etiology of Stargardt's disease from the phenotype in abcr knockout mice". Cell 98 (1): 13–23. doi:10.1016/S0092-8674(00)80602-9. PMID 10412977.
- Molday RS, Beharry S, Ahn J, Zhong M (2006). Binding of N-Retinylidene-Pe to BACA4 and a Model for its Transport Across Membranes. "Binding of N-retinylidene-PE to ABCA4 and a model for its transport across membranes". Advances in Experimental Medicine and Biology. Advances in Experimental Medicine and Biology 572: 465–70. doi:10.1007/0-387-32442-9_64. ISBN 978-0-387-28464-4. PMID 17249610.
- Maeda A, Maeda T, Golczak M, Palczewski K (September 2008). "Retinopathy in mice induced by disrupted all-trans-retinal clearance". The Journal of Biological Chemistry 283 (39): 26684–93. doi:10.1074/jbc.M804505200. PMC 2546559. PMID 18658157.
- Dixon MJ, Marazita ML, Beaty TH, Murray JC (March 2011). "Cleft lip and palate: understanding genetic and environmental influences". Nat. Rev. Genet. 12 (3): 167–78. doi:10.1038/nrg2933. PMC 3086810. PMID 21331089.
- Beaty TH, Ruczinski I, Murray JC, Marazita ML, Munger RG, Hetmanski JB, Murray T, Redett RJ, Fallin MD, Liang KY, Wu T, Patel PJ, Jin SC, Zhang TX, Schwender H, Wu-Chou YH, Chen PK, Chong SS, Cheah F, Yeow V, Ye X, Wang H, Huang S, Jabs EW, Shi B, Wilcox AJ, Lie RT, Jee SH, Christensen K, Doheny KF, Pugh EW, Ling H, Scott AF (September 2011). "Evidence for gene-environment interaction in a genome wide study of nonsyndromic cleft palate". Genet. Epidemiol. 35 (6): 469–78. doi:10.1002/gepi.20595. PMC 3180858. PMID 21618603.
- Leslie EJ, Mansilla MA, Biggs LC, Schuette K, Bullard S, Cooper M, Dunnwald M, Lidral AC, Marazita ML, Beaty TH, Murray JC (2012). Expression and mutation analyses implicate ARHGAP29 as the etiologic gene for the cleft lip with or without cleft palate locus identified by genome wide association on chromosome 1p22. pp. 1–24.
- MacDonald IM (2006). "Genetic aspects of age-related macular degeneration". Can. J. Ophthalmol. 40 (3): 288–92. doi:10.1139/i05-002. PMID 15947798.
- Bonaldo MF, Lennon G, Soares MB (1997). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Res. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548.
- Allikmets R, Singh N, Sun H, et al. (1997). "A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy". Nat. Genet. 15 (3): 236–46. doi:10.1038/ng0397-236. PMID 9054934.
- Martínez-Mir A, Bayés M, Vilageliu L, et al. (1997). "A new locus for autosomal recessive retinitis pigmentosa (RP19) maps to 1p13-1p21". Genomics 40 (1): 142–6. doi:10.1006/geno.1996.4528. PMID 9070931.
- Azarian SM, Travis GH (1997). "The photoreceptor rim protein is an ABC transporter encoded by the gene for recessive Stargardt's disease (ABCR)". FEBS Lett. 409 (2): 247–52. doi:10.1016/S0014-5793(97)00517-6. PMID 9202155.
- Sun H, Nathans J (1997). "Stargardt's ABCR is localized to the disc membrane of retinal rod outer segments". Nat. Genet. 17 (1): 15–6. doi:10.1038/ng0997-15. PMID 9288089.
- Allikmets R (1997). "A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy". Nat. Genet. 17 (1): 122. doi:10.1038/ng0997-122a. PMID 9288113.
- Allikmets R, Shroyer NF, Singh N, et al. (1997). "Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration". Science 277 (5333): 1805–7. doi:10.1126/science.277.5333.1805. PMID 9295268.
- Martínez-Mir A, Paloma E, Allikmets R, et al. (1998). "Retinitis pigmentosa caused by a homozygous mutation in the Stargardt disease gene ABCR". Nat. Genet. 18 (1): 11–2. doi:10.1038/ng0198-11. PMID 9425888.
- Cremers FP, van de Pol DJ, van Driel M, et al. (1998). "Autosomal recessive retinitis pigmentosa and cone-rod dystrophy caused by splice site mutations in the Stargardt's disease gene ABCR". Hum. Mol. Genet. 7 (3): 355–62. doi:10.1093/hmg/7.3.355. PMID 9466990.
- Nasonkin I, Illing M, Koehler MR, et al. (1998). "Mapping of the rod photoreceptor ABC transporter (ABCR) to 1p21-p22.1 and identification of novel mutations in Stargardt's disease". Hum. Genet. 102 (1): 21–6. doi:10.1007/s004390050649. PMID 9490294.
- Gerber S, Rozet JM, van de Pol TJ, et al. (1998). "Complete exon-intron structure of the retina-specific ATP binding transporter gene (ABCR) allows the identification of novel mutations underlying Stargardt disease". Genomics 48 (1): 139–42. doi:10.1006/geno.1997.5164. PMID 9503029.
- Azarian SM, Megarity CF, Weng J, et al. (1998). "The human photoreceptor rim protein gene (ABCR): genomic structure and primer set information for mutation analysis". Hum. Genet. 102 (6): 699–705. doi:10.1007/s004390050765. PMID 9703434.
- Rozet JM, Gerber S, Souied E, et al. (1998). "Spectrum of ABCR gene mutations in autosomal recessive macular dystrophies". Eur. J. Hum. Genet. 6 (3): 291–5. doi:10.1038/sj.ejhg/5200221. PMID 9781034.
- Lewis RA, Shroyer NF, Singh N, et al. (1999). "Genotype/Phenotype analysis of a photoreceptor-specific ATP-binding cassette transporter gene, ABCR, in Stargardt disease". Am. J. Hum. Genet. 64 (2): 422–34. doi:10.1086/302251. PMC 1377752. PMID 9973280.
- Sun H, Molday RS, Nathans J (1999). "Retinal stimulates ATP hydrolysis by purified and reconstituted ABCR, the photoreceptor-specific ATP-binding cassette transporter responsible for Stargardt disease". J. Biol. Chem. 274 (12): 8269–81. doi:10.1074/jbc.274.12.8269. PMID 10075733.
- Maugeri A, van Driel MA, van de Pol DJ, et al. (2000). "The 2588G→C mutation in the ABCR gene is a mild frequent founder mutation in the Western European population and allows the classification of ABCR mutations in patients with Stargardt disease". Am. J. Hum. Genet. 64 (4): 1024–35. doi:10.1086/302323. PMC 1377826. PMID 10090887.
- Fishman GA, Stone EM, Grover S, et al. (1999). "Variation of clinical expression in patients with Stargardt dystrophy and sequence variations in the ABCR gene". Arch. Ophthalmol. 117 (4): 504–10. PMID 10206579.
- Körschen HG, Beyermann M, Müller F, et al. (1999). "Interaction of glutamic-acid-rich proteins with the cGMP signalling pathway in rod photoreceptors". Nature 400 (6746): 761–6. doi:10.1038/23468. PMID 10466724.
- Zhang K, Garibaldi DC, Kniazeva M, et al. (1999). "A novel mutation in the ABCR gene in four patients with autosomal recessive Stargardt disease". Am. J. Ophthalmol. 128 (6): 720–4. doi:10.1016/S0002-9394(99)00236-6. PMID 10612508.
- GeneReviews/NIH/NCBI/UW entry on Retinitis Pigmentosa Overview
- ABCA4 protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)
- ABCA4 human gene location in the UCSC Genome Browser.
- ABCA4 human gene details in the UCSC Genome Browser.