ABCA4

ABCA4
识别号
别名	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
相关疾病
	斯特格病、age related macular degeneration 2、cone-rod dystrophy 3、retinitis pigmentosa 19、老年黄斑变性、cone-rod dystrophy
基因位置（人类）
染色体	1号染色体
终止	94,121,148 bp
基因位置（小鼠）
染色体	小鼠3号染色体
终止	121,973,772 bp
RNA表达模式
	查阅更多表达数据
基因本体
分子功能	• ATPase-coupled transmembrane transporter activity; • 核苷酸结合; • phospholipid transporter activity; • ATPase-coupled intramembrane lipid transporter activity; • ATP结合; • phosphatidylethanolamine flippase activity; • ATPase activity; • transporter activity; • lipid transporter activity;
细胞组分	• integral component of membrane; • 细胞内膜结合细胞器; • 膜; • photoreceptor outer segment; • integral component of plasma membrane; • photoreceptor disc membrane; • 内质网;
生物学过程	• response to stimulus; • phospholipid transfer to membrane; • retinoid metabolic process; • phototransduction, visible light; • photoreceptor cell maintenance; • 视觉; • 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
	维基数据
查看/编辑人类	查看/编辑小鼠

三磷酸腺苷结合盒亚家族A成员4（英语：ATP-binding cassette, sub-family A, member 4），也称为ABCA4或ABCR，是一种在人类中由ABCA4基因编码的蛋白质。^[6]^[7]^[8]

Quick Facts ABCA4, 识别号 ...

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ABCA4是ATP结合盒转运蛋白（ABC）基因亚家族A的成员，仅存在于多细胞真核生物中。^[6]该基因于1997年首次被克隆并鉴定为导致斯特格氏病的基因，斯特格氏病是一种导致黄斑变性的常染色体隐性遗传病。^[9]ABCA4基因转录具有两个跨膜结构域（TMD）、两个糖基化细胞外结构域（ECD）和两个核苷酸结合结构域（NBD）的大型视网膜特异性蛋白。ABCA4蛋白几乎只在视网膜中表达，定位于视杆细胞的外段圆盘边缘。^[10]

结构

以前称为光感受器边缘蛋白RmP或ABCA4，最近提出的ABCA4结构由两个跨膜结构域（TMD）、两个大的糖基化胞外结构域（ECD）和两个内部核苷酸结合结构域（NBD）组成。一个TMD跨越膜，六个蛋白质单元连接在一起形成一个结构域。因TMD作为通道或配体结合控制器的特异性和多样性，所以其通常在基因组中不保守。然而，NBD在不同基因组中高度保守，这一观察结果与其结合和水解三磷酸腺苷一致。NBD与三磷酸腺苷分子结合，利用高能无机磷酸盐来改变ABC转运蛋白的构象。转录的ABCA4形成异二聚体：通道的两个二聚体隔室彼此不同。当TMD位于膜中时，它们形成桶状结构，可渗透视黄醇配体并控制通道进入其结合位点。^[11]一旦三磷酸腺苷在通道的NBD处水解，NBD就会聚集在一起以倾斜和修饰TMD以调节配体与通道的结合。^[12]最近提出的类视黄醇转移模型是由于外部和内部TMD配体结合位点的交替暴露而发生的，所有这些都由三磷酸腺苷的结合控制，是基于最近对细菌ABC转运蛋白的结构分析。

功能

ABCA4局限于杆和锥的外段盘边缘。ABCA4的表达比视紫红质少得多，大约为1:120。哺乳动物ABCA4与其他ABC的比较、ABCA4的细胞定位以及ABCA4基因敲除小鼠的分析表明ABCA4可能作为一种内向的类视黄醇翻转酶发挥作用。^[13]翻转酶是一种跨膜蛋白，可“翻转”其构象以跨膜运输物质。在ABCA4的情况下，翻转酶促进N-视黄基-磷脂酰乙醇胺（NR-PE）的转移，NR-PE是全反式视黄醛（ATR）与磷脂酰乙醇胺（PE）的共价加合物，作为带电物质被困在圆盘内，进入细胞质表面。^[14]一旦运输，ATR被还原为维生素A，然后转移到视网膜色素上皮，再循环成11-顺式视黄醛。这种ABCA4的交替访问-释放模型有四个步骤：(1)三磷酸腺苷与NBD的结合，将两个NBD结合在一起，并暴露位于TMD的外前庭高亲和力结合位点，(2)NR-PE/ATR在细胞外的结合通道一侧，(3)三磷酸腺苷水解促进门打开和NR-PE/ATR跨膜移动到TMD细胞内部分的低亲和力结合位点，以及(4)二磷酸腺苷和无机磷酸盐（P_i）释放结合的配体。然后通道准备好再次传输另一个NR-PE/ATR分子。

ABCA4-/-基因敲除小鼠已延迟暗适应，但相对于对照组而言，最终杆状细胞阈值正常。^[13]这表明从细胞外膜去除ATR/NR-PE的大量跨膜扩散途径。用强光漂白视网膜后，ATR/NR-PE在外节显着积累。这种积累导致形成有毒的阳离子双吡啶盐、N-亚视黄基-N-视黄基乙醇胺（A2E），从而导致人类干性和湿性年龄相关性黄斑变性。^[15]从这个实验中，可以得出结论ABCA4在清除ATR/NR-PE的积累方面具有重要作用，以防止在漂白剂恢复过程中在细胞外感光器表面形成A2E。

临床意义

已知ABCA4基因的突变会导致常染色体隐性遗传病斯特格氏黄斑营养不良（STGD），这是一种遗传性青少年黄斑变性病，会导致感光细胞逐渐丧失。STGD的特征是视力和色觉降低、中央（黄斑）视力丧失、暗适应延迟以及自体荧光RPE脂褐素积累。^[16]去除NR-PE/ATR似乎对正常的漂白剂恢复和减轻导致光感受器退化的持久性视蛋白信号具有重要意义。ABCA4还减轻了ATR积累的长期影响，导致不可逆的ATR与第二个ATR分子和NR-PE结合形成二氢-N-亚视黄基-N-视黄基-磷脂酰-乙醇胺（A2PE-H2）。A2PE-H2捕获ATR并在外部片段中积累，以进一步氧化成N-亚视黄基-N-视黄基-磷脂酰-乙醇胺（A2PE）。在RPE细胞昼夜盘脱落和吞噬外节后，A2PE在RPE吞噬溶酶体内水解形成A2E。^[16]A2E的积累会导致原发性RPE水平的毒性和黄斑变性中的继发性光感受器破坏。

可能与ABCA4突变相关的其他疾病包括视锥细胞营养不良、视网膜色素变性和年龄相关性黄斑变性。

GENEVA Cleft Consortium研究首先确定ABCA4与唇裂和/或腭裂有关，并通过多个标记提供了全基因组显着性水平的连锁和关联证据。^[17]尽管该基因中的SNP与唇裂/腭裂有关，但没有功能或表达数据支持它作为致病基因，相反，它可能位于与ABCA4相邻的区域。^[18]全基因组关联、罕见编码序列变异、颅面特异性表达以及与 IRF6 的相互作用的组合支持相邻的ARHGAP29基因可能是在非综合征性唇裂和/或腭裂中发挥作用的致病基因。^[19]

参见

ATP结合盒转运蛋白

参考资料

[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. （原始内容存档于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 引用错误：没有为名为maeda2008的参考文献提供内容
[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.

延申阅读

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.
Bonaldo MF, Lennon G, Soares MB. Normalization and subtraction: two approaches to facilitate gene discovery. Genome Research. September 1996, 6 (9): 791–806. PMID 8889548. doi:10.1101/gr.6.9.791 .
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. （原始内容存档于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 .

外部链接

GeneReviews/NIH/NCBI/UW entry on Retinitis Pigmentosa Overview （页面存档备份，存于互联网档案馆）
医学主题词表（MeSH）：ABCA4+protein,+human
Template:UCSC genome browser
Template:UCSC gene details

Template:ABC转运蛋白

[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. （原始内容存档于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.

[vanmeer2005-11] [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 .

[sullivan2008-12] [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.

[weng19992-13] [13]
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