ABCA4

ABCA4
識別號
別名	ABCA4；, AW050280, Abc10, Abcr, D430003I15Rik, RmP, ARMD2, CORD3, FFM, RP19, STGD, STGD1, ATP binding cassette subfamily A member 4
外部ID	OMIM：601691 MGI：109424 HomoloGene：298 GeneCards：ABCA4
相關疾病
	斯特格病、age related macular degeneration 2、cone-rod dystrophy 3、retinitis pigmentosa 19、老年黃斑變性、cone-rod dystrophy
基因位置（人類）
染色體	1號染色體
終止	94,121,148 bp
基因位置（小鼠）
染色體	小鼠3號染色體
終止	121,973,772 bp
RNA表達模式
	查閱更多表達數據
基因本體
分子功能	• ATPase-coupled transmembrane transporter activity; • 核苷酸結合; • phospholipid transporter activity; • ATPase-coupled intramembrane lipid transporter activity; • ATP結合; • phosphatidylethanolamine flippase activity; • ATPase activity; • transporter activity; • lipid transporter activity;
細胞組分	• integral component of membrane; • 細胞內膜結合細胞器; • 膜; • photoreceptor outer segment; • integral component of plasma membrane; • photoreceptor disc membrane; • 內質網;
生物學過程	• response to stimulus; • phospholipid transfer to membrane; • retinoid metabolic process; • phototransduction, visible light; • photoreceptor cell maintenance; • 視覺; • phospholipid translocation; • lipid transport; • transmembrane transport;
	Sources:Amigo / QuickGO
直系同源
	24
	11304
	ENSG00000198691
	ENSMUSG00000028125
	P78363
	O35600
	NM_000350
	NM_007378
	NP_000341
	NP_031404
	維基數據
檢視/編輯人類	檢視/編輯小鼠

三磷酸腺苷結合盒亞家族A成員4（英語：ATP-binding cassette, sub-family A, member 4），也稱為ABCA4或ABCR，是一種在人類中由ABCA4基因編碼的蛋白質。^[6]^[7]^[8]

Quick Facts ABCA4, 識別號 ...

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ABCA4是ATP結合盒轉運蛋白（ABC）基因亞家族A的成員，僅存在於多細胞真核生物中。^[6]該基因於1997年首次被克隆並鑑定為導致斯特格氏病的基因，斯特格氏病是一種導致黃斑變性的常染色體隱性遺傳病。^[9]ABCA4基因轉錄具有兩個跨膜結構域（TMD）、兩個糖基化細胞外結構域（ECD）和兩個核苷酸結合結構域（NBD）的大型視網膜特異性蛋白。ABCA4蛋白幾乎只在視網膜中表達，定位於視桿細胞的外段圓盤邊緣。^[10]

結構

以前稱為光感受器邊緣蛋白RmP或ABCA4，最近提出的ABCA4結構由兩個跨膜結構域（TMD）、兩個大的糖基化胞外結構域（ECD）和兩個內部核苷酸結合結構域（NBD）組成。一個TMD跨越膜，六個蛋白質單元連接在一起形成一個結構域。因TMD作為通道或配體結合控制器的特異性和多樣性，所以其通常在基因組中不保守。然而，NBD在不同基因組中高度保守，這一觀察結果與其結合和水解三磷酸腺苷一致。NBD與三磷酸腺苷分子結合，利用高能無機磷酸鹽來改變ABC轉運蛋白的構象。轉錄的ABCA4形成異二聚體：通道的兩個二聚體隔室彼此不同。當TMD位於膜中時，它們形成桶狀結構，可滲透視黃醇配體並控制通道進入其結合位點。^[11]一旦三磷酸腺苷在通道的NBD處水解，NBD就會聚集在一起以傾斜和修飾TMD以調節配體與通道的結合。^[12]最近提出的類視黃醇轉移模型是由於外部和內部TMD配體結合位點的交替暴露而發生的，所有這些都由三磷酸腺苷的結合控制，是基於最近對細菌ABC轉運蛋白的結構分析。

功能

ABCA4局限於杆和錐的外段盤邊緣。ABCA4的表達比視紫紅質少得多，大約為1:120。哺乳動物ABCA4與其他ABC的比較、ABCA4的細胞定位以及ABCA4基因敲除小鼠的分析表明ABCA4可能作為一種內向的類視黃醇翻轉酶發揮作用。^[13]翻轉酶是一種跨膜蛋白，可「翻轉」其構象以跨膜運輸物質。在ABCA4的情況下，翻轉酶促進N-視黃基-磷脂酰乙醇胺（NR-PE）的轉移，NR-PE是全反式視黃醛（ATR）與磷脂酰乙醇胺（PE）的共價加合物，作為帶電物質被困在圓盤內，進入細胞質表面。^[14]一旦運輸，ATR被還原為維他命A，然後轉移到視網膜色素上皮，再循環成11-順式視黃醛。這種ABCA4的交替訪問-釋放模型有四個步驟：(1)三磷酸腺苷與NBD的結合，將兩個NBD結合在一起，並暴露位於TMD的外前庭高親和力結合位點，(2)NR-PE/ATR在細胞外的結合通道一側，(3)三磷酸腺苷水解促進門打開和NR-PE/ATR跨膜移動到TMD細胞內部分的低親和力結合位點，以及(4)二磷酸腺苷和無機磷酸鹽（P_i）釋放結合的配體。然後通道準備好再次傳輸另一個NR-PE/ATR分子。

ABCA4-/-基因敲除小鼠已延遲暗適應，但相對於對照組而言，最終杆狀細胞閾值正常。^[13]這表明從細胞外膜去除ATR/NR-PE的大量跨膜擴散途徑。用強光漂白視網膜後，ATR/NR-PE在外節顯着積累。這種積累導致形成有毒的陽離子雙吡啶鹽、N-亞視黃基-N-視黃基乙醇胺（A2E），從而導致人類乾性和濕性年齡相關性黃斑變性。^[15]從這個實驗中，可以得出結論ABCA4在清除ATR/NR-PE的積累方面具有重要作用，以防止在漂白劑恢復過程中在細胞外感光器表面形成A2E。

臨床意義

已知ABCA4基因的突變會導致常染色體隱性遺傳病斯特格氏黃斑營養不良（STGD），這是一種遺傳性青少年黃斑變性病，會導致感光細胞逐漸喪失。STGD的特徵是視力和色覺降低、中央（黃斑）視力喪失、暗適應延遲以及自體熒光RPE脂褐素積累。^[16]去除NR-PE/ATR似乎對正常的漂白劑恢復和減輕導致光感受器退化的持久性視蛋白信號具有重要意義。ABCA4還減輕了ATR積累的長期影響，導致不可逆的ATR與第二個ATR分子和NR-PE結合形成二氫-N-亞視黃基-N-視黃基-磷脂酰-乙醇胺（A2PE-H2）。A2PE-H2捕獲ATR並在外部片段中積累，以進一步氧化成N-亞視黃基-N-視黃基-磷脂酰-乙醇胺（A2PE）。在RPE細胞晝夜盤脫落和吞噬外節後，A2PE在RPE吞噬溶酶體內水解形成A2E。^[16]A2E的積累會導致原發性RPE水平的毒性和黃斑變性中的繼發性光感受器破壞。

可能與ABCA4突變相關的其他疾病包括視錐細胞營養不良、視網膜色素變性和年齡相關性黃斑變性。

GENEVA Cleft Consortium研究首先確定ABCA4與唇裂和/或齶裂有關，並通過多個標記提供了全基因組顯着性水平的連鎖和關聯證據。^[17]儘管該基因中的SNP與唇裂/齶裂有關，但沒有功能或表達數據支持它作為致病基因，相反，它可能位於與ABCA4相鄰的區域。^[18]全基因組關聯、罕見編碼序列變異、顱面特異性表達以及與 IRF6 的相互作用的組合支持相鄰的ARHGAP29基因可能是在非綜合症性唇裂和/或齶裂中發揮作用的致病基因。^[19]

參見

ATP結合盒轉運蛋白

參考資料

[1]
與ABCA4相關的疾病；在維基數據上查看/編輯參考.
[2]
GRCh38: Ensembl release 89: ENSG00000198691 - Ensembl, May 2017
[3]
GRCm38: Ensembl release 89: ENSMUSG00000028125 - Ensembl, May 2017
[4]
Human PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.
[5]
Mouse PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.
[6]
Entrez Gene: ABCA4 ATP-binding cassette, sub-family A (ABC1), member 4.
[7]
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. A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nature Genetics. March 1997, 15 (3): 236–46. PMID 9054934. S2CID 31677978. doi:10.1038/ng0397-236.
[8]
Nasonkin I, Illing M, Koehler MR, Schmid M, Molday RS, Weber BH. Mapping of the rod photoreceptor ABC transporter (ABCR) to 1p21-p22.1 and identification of novel mutations in Stargardt's disease. Human Genetics. January 1998, 102 (1): 21–6. PMID 9490294. S2CID 22070963. doi:10.1007/s004390050649.
[9]
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. Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration. Science. September 1997, 277 (5333): 1805–7 [2023-01-31]. PMID 9295268. doi:10.1126/science.277.5333.1805. （原始內容存檔於2023-01-31）.
[10]
Sun H, Nathans J. ABCR: rod photoreceptor-specific ABC transporter responsible for Stargardt disease. Methods in Enzymology. 2000, 315: 879–97. ISBN 978-0-12-182216-3. PMID 10736747. doi:10.1016/S0076-6879(00)15888-4.
[11]
van Meer G, Halter D, Sprong H, Somerharju P, Egmond MR. ABC lipid transporters: extruders, flippases, or flopless activators?. FEBS Letters. February 2006, 580 (4): 1171–7. PMID 16376334. S2CID 27946190. doi:10.1016/j.febslet.2005.12.019. hdl:1874/19996 .
[12]
Sullivan JM. Focus on molecules: ABCA4 (ABCR)--an import-directed photoreceptor retinoid flipase. Experimental Eye Research. November 2009, 89 (5): 602–3. PMC 3371273 . PMID 19306869. doi:10.1016/j.exer.2009.03.005.
[13]
Weng J, Mata NL, Azarian SM, Tzekov RT, Birch DG, Travis GH. Insights into the function of Rim protein in photoreceptors and etiology of Stargardt's disease from the phenotype in abcr knockout mice. Cell. July 1999, 98 (1): 13–23. PMID 10412977. S2CID 18605680. doi:10.1016/S0092-8674(00)80602-9 .
[14]
Molday RS, Beharry S, Ahn J, Zhong M. Binding of N-retinylidene-PE to ABCA4 and a model for its transport across membranes. Advances in Experimental Medicine and Biology. 2006, 572: 465–70. ISBN 978-0-387-28464-4. PMID 17249610. doi:10.1007/0-387-32442-9_64.
[15]
Maeda A, Maeda T, Golczak M, Palczewski K. Retinopathy in mice induced by disrupted all-trans-retinal clearance. The Journal of Biological Chemistry. September 2008, 283 (39): 26684–93. PMC 2546559 . PMID 18658157. doi:10.1074/jbc.M804505200 .
^ ^16.0 ^16.1 引用錯誤：沒有為名為maeda2008的參考文獻提供內容
[17]
Dixon MJ, Marazita ML, Beaty TH, Murray JC. Cleft lip and palate: understanding genetic and environmental influences. Nature Reviews Genetics. March 2011, 12 (3): 167–78. PMC 3086810 . PMID 21331089. doi:10.1038/nrg2933.
[18]
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. Evidence for gene-environment interaction in a genome wide study of nonsyndromic cleft palate. Genetic Epidemiology. September 2011, 35 (6): 469–78. PMC 3180858 . PMID 21618603. doi:10.1002/gepi.20595.
[19]
Leslie EJ, Mansilla MA, Biggs LC, Schuette K, Bullard S, Cooper M, Dunnwald M, Lidral AC, Marazita ML, Beaty TH, Murray JC. 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. Birth Defects Research. Part A, Clinical and Molecular Teratology. November 2012, 94 (11): 934–42. PMC 3501616 . PMID 23008150. doi:10.1002/bdra.23076.

延申閱讀

MacDonald IM. Genetic aspects of age-related macular degeneration. Canadian Journal of Ophthalmology. June 2005, 40 (3): 288–92. PMID 15947798. doi:10.1016/S0008-4182(05)80071-7.
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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. A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nature Genetics. March 1997, 15 (3): 236–46. PMID 9054934. S2CID 31677978. doi:10.1038/ng0397-236.
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. A new locus for autosomal recessive retinitis pigmentosa (RP19) maps to 1p13-1p21. Genomics. February 1997, 40 (1): 142–6. PMID 9070931. doi:10.1006/geno.1996.4528. hdl:10261/39369 .
Azarian SM, Travis GH. The photoreceptor rim protein is an ABC transporter encoded by the gene for recessive Stargardt's disease (ABCR). FEBS Letters. June 1997, 409 (2): 247–52. PMID 9202155. doi:10.1016/S0014-5793(97)00517-6 .
Sun H, Nathans J. Stargardt's ABCR is localized to the disc membrane of retinal rod outer segments. Nature Genetics. September 1997, 17 (1): 15–6. PMID 9288089. S2CID 759924. doi:10.1038/ng0997-15.
Allikmets R. A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nature Genetics. September 1997, 17 (1): 122. PMID 9288113. doi:10.1038/ng0997-122a .
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. Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration. Science. September 1997, 277 (5333): 1805–7 [2023-01-31]. PMID 9295268. doi:10.1126/science.277.5333.1805. （原始內容存檔於2023-01-31）.
Martínez-Mir A, Paloma E, Allikmets R, Ayuso C, del Rio T, Dean M, Vilageliu L, Gonzàlez-Duarte R, Balcells S. Retinitis pigmentosa caused by a homozygous mutation in the Stargardt disease gene ABCR. Nature Genetics. January 1998, 18 (1): 11–2. PMID 9425888. S2CID 125620. doi:10.1038/ng0198-11. hdl:10261/39477 .
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. Autosomal recessive retinitis pigmentosa and cone-rod dystrophy caused by splice site mutations in the Stargardt's disease gene ABCR. Human Molecular Genetics. March 1998, 7 (3): 355–62. PMID 9466990. doi:10.1093/hmg/7.3.355 .
Nasonkin I, Illing M, Koehler MR, Schmid M, Molday RS, Weber BH. Mapping of the rod photoreceptor ABC transporter (ABCR) to 1p21-p22.1 and identification of novel mutations in Stargardt's disease. Human Genetics. January 1998, 102 (1): 21–6. PMID 9490294. S2CID 22070963. doi:10.1007/s004390050649.
Gerber S, Rozet JM, van de Pol TJ, Hoyng CB, Munnich A, Blankenagel A, Kaplan J, Cremers FP. Complete exon-intron structure of the retina-specific ATP binding transporter gene (ABCR) allows the identification of novel mutations underlying Stargardt disease. Genomics. February 1998, 48 (1): 139–42. PMID 9503029. doi:10.1006/geno.1997.5164.
Azarian SM, Megarity CF, Weng J, Horvath DH, Travis GH. The human photoreceptor rim protein gene (ABCR): genomic structure and primer set information for mutation analysis. Human Genetics. June 1998, 102 (6): 699–705. PMID 9703434. S2CID 34452470. doi:10.1007/s004390050765.
Rozet JM, Gerber S, Souied E, Perrault I, Châtelin S, Ghazi I, Leowski C, Dufier JL, Munnich A, Kaplan J. Spectrum of ABCR gene mutations in autosomal recessive macular dystrophies. European Journal of Human Genetics. 1998, 6 (3): 291–5. PMID 9781034. doi:10.1038/sj.ejhg.5200221 .
Lewis RA, Shroyer NF, Singh N, Allikmets R, Hutchinson A, Li Y, Lupski JR, Leppert M, Dean M. Genotype/Phenotype analysis of a photoreceptor-specific ATP-binding cassette transporter gene, ABCR, in Stargardt disease. American Journal of Human Genetics. February 1999, 64 (2): 422–34. PMC 1377752 . PMID 9973280. doi:10.1086/302251.
Sun H, Molday RS, Nathans J. Retinal stimulates ATP hydrolysis by purified and reconstituted ABCR, the photoreceptor-specific ATP-binding cassette transporter responsible for Stargardt disease. The Journal of Biological Chemistry. March 1999, 274 (12): 8269–81. PMID 10075733. doi:10.1074/jbc.274.12.8269 .
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. 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. American Journal of Human Genetics. April 1999, 64 (4): 1024–35. PMC 1377826 . PMID 10090887. doi:10.1086/302323.
Fishman GA, Stone EM, Grover S, Derlacki DJ, Haines HL, Hockey RR. Variation of clinical expression in patients with Stargardt dystrophy and sequence variations in the ABCR gene. Archives of Ophthalmology. April 1999, 117 (4): 504–10. PMID 10206579. doi:10.1001/archopht.117.4.504 .
Körschen HG, Beyermann M, Müller F, Heck M, Vantler M, Koch KW, Kellner R, Wolfrum U, Bode C, Hofmann KP, Kaupp UB. Interaction of glutamic-acid-rich proteins with the cGMP signalling pathway in rod photoreceptors. Nature. August 1999, 400 (6746): 761–6. Bibcode:1999Natur.400..761K. PMID 10466724. S2CID 4394997. doi:10.1038/23468.
Zhang K, Garibaldi DC, Kniazeva M, Albini T, Chiang MF, Kerrigan M, Sunness JS, Han M, Allikmets R. A novel mutation in the ABCR gene in four patients with autosomal recessive Stargardt disease. American Journal of Ophthalmology. December 1999, 128 (6): 720–4. PMID 10612508. doi:10.1016/S0002-9394(99)00236-6 .

外部連結

GeneReviews/NIH/NCBI/UW entry on Retinitis Pigmentosa Overview （頁面存檔備份，存於互聯網檔案館）
醫學主題詞表（MeSH）：ABCA4+protein,+human
Template:UCSC genome browser
Template:UCSC gene details

Template:ABC轉運蛋白

[1] [1]
與ABCA4相關的疾病；在維基數據上查看/編輯參考.

[refGRCh38Ensembl-2] [2]
GRCh38: Ensembl release 89: ENSG00000198691 - Ensembl, May 2017

[refGRCm38Ensembl-3] [3]
GRCm38: Ensembl release 89: ENSMUSG00000028125 - Ensembl, May 2017

[4] [4]
Human PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.

[5] [5]
Mouse PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.

[entrez-6] [6]
Entrez Gene: ABCA4 ATP-binding cassette, sub-family A (ABC1), member 4.

[pmid9054934-7] [7]
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. A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nature Genetics. March 1997, 15 (3): 236–46. PMID 9054934. S2CID 31677978. doi:10.1038/ng0397-236.

[pmid9490294-8] [8]
Nasonkin I, Illing M, Koehler MR, Schmid M, Molday RS, Weber BH. Mapping of the rod photoreceptor ABC transporter (ABCR) to 1p21-p22.1 and identification of novel mutations in Stargardt's disease. Human Genetics. January 1998, 102 (1): 21–6. PMID 9490294. S2CID 22070963. doi:10.1007/s004390050649.

[pmid9295268-9] [9]
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. Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration. Science. September 1997, 277 (5333): 1805–7 [2023-01-31]. PMID 9295268. doi:10.1126/science.277.5333.1805. （原始內容存檔於2023-01-31）.

[pmid10736747-10] [10]
Sun H, Nathans J. ABCR: rod photoreceptor-specific ABC transporter responsible for Stargardt disease. Methods in Enzymology. 2000, 315: 879–97. ISBN 978-0-12-182216-3. PMID 10736747. doi:10.1016/S0076-6879(00)15888-4.

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