# ABCA4 > Mediated Wiki article. Canonical URL: https://mediated.wiki/source/ABCA4 > Markdown URL: https://mediated.wiki/source/ABCA4.md > Source: https://en.wikipedia.org/wiki/ABCA4 > Source revision: 1306707146 > License: Creative Commons Attribution-ShareAlike 4.0 International (https://creativecommons.org/licenses/by-sa/4.0/) {{Short description|Mammalian protein found in humans}} {{cs1 config|name-list-style=vanc}} {{Infobox gene}} '''ATP-binding cassette, sub-family A (ABC1), member 4''', also known as '''ABCA4''' or '''ABCR''', is a [protein](/source/protein) which in humans is encoded by the ''ABCA4'' [gene](/source/gene).{{cite web | title = Entrez Gene: ABCA4 ATP-binding cassette, sub-family A (ABC1), member 4| url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=24}}{{cite journal | vauthors = 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 | title = A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy | journal = Nature Genetics | volume = 15 | issue = 3 | pages = 236–46 | date = March 1997 | pmid = 9054934 | doi = 10.1038/ng0397-236 | s2cid = 31677978 }}{{cite journal | vauthors = Nasonkin I, Illing M, Koehler MR, Schmid M, Molday RS, Weber BH | title = Mapping of the rod photoreceptor ABC transporter (ABCR) to 1p21-p22.1 and identification of novel mutations in Stargardt's disease | journal = Human Genetics | volume = 102 | issue = 1 | pages = 21–6 | date = January 1998 | pmid = 9490294 | doi = 10.1007/s004390050649 | s2cid = 22070963 }} ABCA4 is a member of the [ATP-binding cassette transporter](/source/ATP-binding_cassette_transporter) gene sub-family A (ABC1) found exclusively in multicellular [eukaryote](/source/eukaryote)s. The gene was first cloned and characterized in 1997 as a gene that causes [Stargardt disease](/source/Stargardt_disease), an autosomal recessive disease that causes [macular degeneration](/source/macular_degeneration).{{cite journal | vauthors = 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 | title = Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration | journal = Science | volume = 277 | issue = 5333 | pages = 1805–7 | date = September 1997 | pmid = 9295268 | doi = 10.1126/science.277.5333.1805 | url = https://zenodo.org/record/1231124 }} The ''ABCA4'' gene transcribes a large retina-specific protein with two transmembrane domains (TMD), two [glycosylated](/source/glycosylation) extracellular [domain](/source/protein_domain)s (ECD), and two [nucleotide](/source/nucleotide)-binding domains (NBD). The ABCA4 protein is almost exclusively expressed in [retina](/source/retina) localizing in outer segment disk edges of [rod photoreceptor](/source/photoreceptor_cell)s.{{cite book | vauthors = Sun H, Nathans J | chapter = ABCR: Rod photoreceptor-specific ABC transporter responsible for Stargardt disease | title = Vertebrate Phototransduction and the Visual Cycle, Part A | series = Methods in Enzymology | volume = 315 | pages = [https://archive.org/details/vertebratephotot0315unse/page/879 879–97] | year = 2000 | pmid = 10736747 | doi = 10.1016/S0076-6879(00)15888-4 | isbn = 978-0-12-182216-3 | chapter-url = https://archive.org/details/vertebratephotot0315unse/page/879 }} == Structure == Previously known as the photoreceptor rim protein RmP or ABCR, the recently proposed ABCA4 structure consists of two transmembrane domains (TMDs), two large glycosylated extracytosolic 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](/source/adenosine_triphosphate) molecules (ATP) to utilize the high-energy inorganic [phosphate](/source/phosphate) to carry out change in conformation of the ABC transporter. Transcribed ''ABCA4'' forms into a [heterodimer](/source/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](/source/retinoid) ligands and control channel access to its binding sites.{{cite journal | vauthors = van Meer G, Halter D, Sprong H, Somerharju P, Egmond MR | title = ABC lipid transporters: extruders, flippases, or flopless activators? | journal = FEBS Letters | volume = 580 | issue = 4 | pages = 1171–7 | date = February 2006 | pmid = 16376334 | doi = 10.1016/j.febslet.2005.12.019 | bibcode = 2006FEBSL.580.1171V | hdl = 1874/19996 | s2cid = 27946190 | hdl-access = free }} 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.{{cite journal | vauthors = Sullivan JM | title = Focus on molecules: ABCA4 (ABCR)--an import-directed photoreceptor retinoid flipase | journal = Experimental Eye Research | volume = 89 | issue = 5 | pages = 602–3 | date = November 2009 | pmid = 19306869 | pmc = 3371273 | doi = 10.1016/j.exer.2009.03.005 }} 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. == Function == ''ABCR'' is localized to outer segment disk edges of [rod](/source/rod_cell)s and [cone](/source/cone_cell)s. ''ABCR'' is expressed much less than [rhodopsin](/source/rhodopsin), approximately at 1:120. Comparisons between mammalian ''ABCA4'' to other ABCs, cellular localization of ABCA4, and analyses of ABCA4 [knockout mice](/source/knockout_mice) suggest that ABCA4 may function as an inward-directed retinoid [flippase](/source/flippase).{{cite journal | vauthors = Weng J, Mata NL, Azarian SM, Tzekov RT, Birch DG, Travis GH | title = Insights into the function of Rim protein in photoreceptors and etiology of Stargardt's disease from the phenotype in abcr knockout mice | journal = Cell | volume = 98 | issue = 1 | pages = 13–23 | date = July 1999 | pmid = 10412977 | doi = 10.1016/S0092-8674(00)80602-9 | s2cid = 18605680 | doi-access = free }} 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](/source/phosphatidylethanolamine) (NR-PE), a covalent adduct of all-trans [retinal](/source/retinal)dehyde (ATR) with phosphatidylethanolamine (PE), trapped inside the disk as charged species out to the cytoplasmic surface.{{cite book | vauthors = Molday RS, Beharry S, Ahn J, Zhong M | title = Binding of N-retinylidene-PE to ABCA4 and a model for its transport across membranes | chapter = Binding of N-Retinylidene-Pe to BACA4 and a Model for its Transport Across Membranes | series = Advances in Experimental Medicine and Biology | volume = 572 | pages = [https://archive.org/details/isbn_9780387284644/page/465 465–70] | year = 2006 | pmid = 17249610 | doi = 10.1007/0-387-32442-9_64 | isbn = 978-0-387-28464-4 | url-access = registration | url = https://archive.org/details/isbn_9780387284644/page/465 }} 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](/source/adenosine_triphosphate) 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](/source/adenosine_diphosphate)) and inorganic [phosphate](/source/phosphate) (Pi) to release the bound ligand. The channel is then ready to transfer another molecule of NR-PE/ATR again. 380px|right|thumb|'''''N''-retinylidene-''N''-retinyl-ethanolamine''' ('''''A2E''''') 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](/source/age-related_macular_degeneration).{{cite journal | vauthors = Maeda A, Maeda T, Golczak M, Palczewski K | title = Retinopathy in mice induced by disrupted all-trans-retinal clearance | journal = The Journal of Biological Chemistry | volume = 283 | issue = 39 | pages = 26684–93 | date = September 2008 | pmid = 18658157 | pmc = 2546559 | doi = 10.1074/jbc.M804505200 | doi-access = free }} 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. == Clinical significance == Mutations in ''ABCA4'' gene are known to cause the autosomal-recessive disease Stargardt macular dystrophy (STGD), which is a hereditary juvenile [macular degeneration](/source/macular_degeneration) disease causing progressive loss of photoreceptor cells. STGD is characterized by reduced visual acuity and color vision, loss of central (macular) vision, delayed dark adaptation, and accumulation of autofluorescent RPE lipofuscin. Removal of NR-PE/ATR appears to be significant in normal bleach recovery and to mitigate persistent [opsin](/source/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. Additional diseases that may link to mutations in ''ABCA4'' include [fundus flavimaculatus](/source/fundus_flavimaculatus), [cone-rod dystrophy](/source/cone-rod_dystrophy), [retinitis pigmentosa](/source/retinitis_pigmentosa), and [age-related macular degeneration](/source/age-related_macular_degeneration). The GENEVA Cleft Consortium study first identified ABCA4 as being associated with [cleft lip](/source/cleft_lip) and/or [cleft palate](/source/cleft_palate) with multiple markers giving evidence of linkage and association at the genome-wide significance level.{{cite journal | vauthors = Dixon MJ, Marazita ML, Beaty TH, Murray JC | title = Cleft lip and palate: understanding genetic and environmental influences | journal = Nature Reviews Genetics | volume = 12 | issue = 3 | pages = 167–78 | date = March 2011 | pmid = 21331089 | pmc = 3086810 | doi = 10.1038/nrg2933 }} Although SNPs in this gene are associated with cleft lip/palate there is no functional or expression data to support it as the causal gene which may, instead, lie in a region adjacent to ABCA4.{{cite journal | vauthors = 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 | title = Evidence for gene-environment interaction in a genome wide study of nonsyndromic cleft palate | journal = Genetic Epidemiology | volume = 35 | issue = 6 | pages = 469–78 | date = September 2011 | pmid = 21618603 | pmc = 3180858 | doi = 10.1002/gepi.20595 }} A combination of [genome wide association](/source/genome_wide_association), rare coding sequence variants, craniofacial specific expression, and interactions with [IRF6](/source/IRF6) support a role for the adjacent [ARHGAP29](/source/ARHGAP29) gene to be the likely causal gene playing a role in nonsyndromic cleft lip and/or palate.{{cite journal | vauthors = Leslie EJ, Mansilla MA, Biggs LC, Schuette K, Bullard S, Cooper M, Dunnwald M, Lidral AC, Marazita ML, Beaty TH, Murray JC | title = 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 | journal = Birth Defects Research. Part A, Clinical and Molecular Teratology | volume = 94 | issue = 11 | pages = 934–42 | date = November 2012 | pmid = 23008150 | doi = 10.1002/bdra.23076 | pmc=3501616}} == See also == * [ATP-binding cassette transporter](/source/ATP-binding_cassette_transporter) == References == {{Reflist|33em}} == Further reading == {{Refbegin|33em}} * {{cite journal | vauthors = MacDonald IM | title = Genetic aspects of age-related macular degeneration | journal = Canadian Journal of Ophthalmology | volume = 40 | issue = 3 | pages = 288–92 | date = June 2005 | pmid = 15947798 | doi = 10.1016/S0008-4182(05)80071-7 }} * {{cite journal | vauthors = Bonaldo MF, Lennon G, Soares MB | title = Normalization and subtraction: two approaches to facilitate gene discovery | journal = Genome Research | volume = 6 | issue = 9 | pages = 791–806 | date = September 1996 | pmid = 8889548 | doi = 10.1101/gr.6.9.791 | doi-access = free }} * {{cite journal | vauthors = 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 | title = A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy | journal = Nature Genetics | volume = 15 | issue = 3 | pages = 236–46 | date = March 1997 | pmid = 9054934 | doi = 10.1038/ng0397-236 | s2cid = 31677978 }} * {{cite journal | vauthors = Martínez-Mir A, Bayés M, Vilageliu L, Grinberg D, Ayuso C, del Río T, García-Sandoval B, Bussaglia E, Baiget M, Gonzàlez-Duarte R, Balcells S | title = A new locus for autosomal recessive retinitis pigmentosa (RP19) maps to 1p13-1p21 | journal = Genomics | volume = 40 | issue = 1 | pages = 142–6 | date = February 1997 | pmid = 9070931 | doi = 10.1006/geno.1996.4528 | hdl = 10261/39369 | hdl-access = free }} * {{cite journal | vauthors = Azarian SM, Travis GH | title = The photoreceptor rim protein is an ABC transporter encoded by the gene for recessive Stargardt's disease (ABCR) | journal = FEBS Letters | volume = 409 | issue = 2 | pages = 247–52 | date = June 1997 | pmid = 9202155 | doi = 10.1016/S0014-5793(97)00517-6 | s2cid = 7701478 | doi-access = | bibcode = 1997FEBSL.409..247A }} * {{cite journal | vauthors = Sun H, Nathans J | title = Stargardt's ABCR is localized to the disc membrane of retinal rod outer segments | journal = Nature Genetics | volume = 17 | issue = 1 | pages = 15–6 | date = September 1997 | pmid = 9288089 | doi = 10.1038/ng0997-15 | s2cid = 759924 }} * {{cite journal | vauthors = Allikmets R | title = A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy | journal = Nature Genetics | volume = 17 | issue = 1 | pages = 122 | date = September 1997 | pmid = 9288113 | doi = 10.1038/ng0997-122a | doi-access = free }} * {{cite journal | vauthors = 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 | title = Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration | journal = Science | volume = 277 | issue = 5333 | pages = 1805–7 | date = September 1997 | pmid = 9295268 | doi = 10.1126/science.277.5333.1805 | url = https://zenodo.org/record/1231124 }} * {{cite journal | vauthors = Martínez-Mir A, Paloma E, Allikmets R, Ayuso C, del Rio T, Dean M, Vilageliu L, Gonzàlez-Duarte R, Balcells S | title = Retinitis pigmentosa caused by a homozygous mutation in the Stargardt disease gene ABCR | journal = Nature Genetics | volume = 18 | issue = 1 | pages = 11–2 | date = January 1998 | pmid = 9425888 | doi = 10.1038/ng0198-11 | hdl = 10261/39477 | s2cid = 125620 | hdl-access = free }} * {{cite journal | vauthors = Cremers FP, van de Pol DJ, van Driel M, den Hollander AI, van Haren FJ, Knoers NV, Tijmes N, Bergen AA, Rohrschneider K, Blankenagel A, Pinckers AJ, Deutman AF, Hoyng CB | title = Autosomal recessive retinitis pigmentosa and cone-rod dystrophy caused by splice site mutations in the Stargardt's disease gene ABCR | journal = Human Molecular Genetics | volume = 7 | issue = 3 | pages = 355–62 | date = March 1998 | pmid = 9466990 | doi = 10.1093/hmg/7.3.355 | doi-access = free }} * {{cite journal | vauthors = Nasonkin I, Illing M, Koehler MR, Schmid M, Molday RS, Weber BH | title = Mapping of the rod photoreceptor ABC transporter (ABCR) to 1p21-p22.1 and identification of novel mutations in Stargardt's disease | journal = Human Genetics | volume = 102 | issue = 1 | pages = 21–6 | date = January 1998 | pmid = 9490294 | doi = 10.1007/s004390050649 | s2cid = 22070963 }} * {{cite journal | vauthors = Gerber S, Rozet JM, van de Pol TJ, Hoyng CB, Munnich A, Blankenagel A, Kaplan J, Cremers FP | title = Complete exon-intron structure of the retina-specific ATP binding transporter gene (ABCR) allows the identification of novel mutations underlying Stargardt disease | journal = Genomics | volume = 48 | issue = 1 | pages = 139–42 | date = February 1998 | pmid = 9503029 | doi = 10.1006/geno.1997.5164 }} * {{cite journal | vauthors = Azarian SM, Megarity CF, Weng J, Horvath DH, Travis GH | title = The human photoreceptor rim protein gene (ABCR): genomic structure and primer set information for mutation analysis | journal = Human Genetics | volume = 102 | issue = 6 | pages = 699–705 | date = June 1998 | pmid = 9703434 | doi = 10.1007/s004390050765 | s2cid = 34452470 }} * {{cite journal | vauthors = Rozet JM, Gerber S, Souied E, Perrault I, Châtelin S, Ghazi I, Leowski C, Dufier JL, Munnich A, Kaplan J | title = Spectrum of ABCR gene mutations in autosomal recessive macular dystrophies | journal = European Journal of Human Genetics | volume = 6 | issue = 3 | pages = 291–5 | year = 1998 | pmid = 9781034 | doi = 10.1038/sj.ejhg.5200221 | doi-access = free }} * {{cite journal | vauthors = Lewis RA, Shroyer NF, Singh N, Allikmets R, Hutchinson A, Li Y, Lupski JR, Leppert M, Dean M | title = Genotype/Phenotype analysis of a photoreceptor-specific ATP-binding cassette transporter gene, ABCR, in Stargardt disease | journal = American Journal of Human Genetics | volume = 64 | issue = 2 | pages = 422–34 | date = February 1999 | pmid = 9973280 | pmc = 1377752 | doi = 10.1086/302251 }} * {{cite journal | vauthors = Sun H, Molday RS, Nathans J | title = Retinal stimulates ATP hydrolysis by purified and reconstituted ABCR, the photoreceptor-specific ATP-binding cassette transporter responsible for Stargardt disease | journal = The Journal of Biological Chemistry | volume = 274 | issue = 12 | pages = 8269–81 | date = March 1999 | pmid = 10075733 | doi = 10.1074/jbc.274.12.8269 | doi-access = free }} * {{cite journal | vauthors = Maugeri A, van Driel MA, van de Pol DJ, Klevering BJ, van Haren FJ, Tijmes N, Bergen AA, Rohrschneider K, Blankenagel A, Pinckers AJ, Dahl N, Brunner HG, Deutman AF, Hoyng CB, Cremers FP | title = 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 | journal = American Journal of Human Genetics | volume = 64 | issue = 4 | pages = 1024–35 | date = April 1999 | pmid = 10090887 | pmc = 1377826 | doi = 10.1086/302323 }} * {{cite journal | vauthors = Fishman GA, Stone EM, Grover S, Derlacki DJ, Haines HL, Hockey RR | title = Variation of clinical expression in patients with Stargardt dystrophy and sequence variations in the ABCR gene | journal = Archives of Ophthalmology | volume = 117 | issue = 4 | pages = 504–10 | date = April 1999 | pmid = 10206579 | doi = 10.1001/archopht.117.4.504 | doi-access = free }} * {{cite journal | vauthors = Körschen HG, Beyermann M, Müller F, Heck M, Vantler M, Koch KW, Kellner R, Wolfrum U, Bode C, Hofmann KP, Kaupp UB | title = Interaction of glutamic-acid-rich proteins with the cGMP signalling pathway in rod photoreceptors | journal = Nature | volume = 400 | issue = 6746 | pages = 761–6 | date = August 1999 | pmid = 10466724 | doi = 10.1038/23468 | bibcode = 1999Natur.400..761K | s2cid = 4394997 }} * {{cite journal | vauthors = Zhang K, Garibaldi DC, Kniazeva M, Albini T, Chiang MF, Kerrigan M, Sunness JS, Han M, Allikmets R | title = A novel mutation in the ABCR gene in four patients with autosomal recessive Stargardt disease | journal = American Journal of Ophthalmology | volume = 128 | issue = 6 | pages = 720–4 | date = December 1999 | pmid = 10612508 | doi = 10.1016/S0002-9394(99)00236-6 | doi-access = free }} {{Refend}} == External links == * [https://www.ncbi.nlm.nih.gov/books/NBK1417/ GeneReviews/NIH/NCBI/UW entry on Retinitis Pigmentosa Overview] * {{MeshName|ABCA4+protein,+human}} * {{UCSC genome browser|ABCA4}} * {{UCSC gene details|ABCA4}} {{NLM content}} {{ABC transporters}} {{Use dmy dates|date=April 2017}} {{DEFAULTSORT:Abca4}} Category:ATP-binding cassette transporters --- Adapted from the Wikipedia article [ABCA4](https://en.wikipedia.org/wiki/ABCA4) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/ABCA4?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.