ABCA4 在视网膜退行性疾病中的作用及治疗

中国临床药理学与治疗学 ›› 2009, Vol. 14 ›› Issue (11): 1201-1207.

• 专论 • 下一篇

ABCA4 在视网膜退行性疾病中的作用及治疗

江冰^1,2, 周宏灏¹

¹中南大学临床药理研究所, 长沙410078, 湖南;
²中南大学湘雅二医院眼科, 长沙410011, 湖南

收稿日期:2009-11-07 修回日期:2009-11-07 发布日期:2020-10-26
作者简介:江冰, 女, 在站博士后, 副教授, 硕士生导师。毕业于湖南医科大学临床医疗系,获中南大学湘雅医学院医学博士学位, 曾在美国爱荷华大学任访问学者一年余;目前在中南大学临床药理研究所从事博士后研究工作, 合作导师为周宏灏院士。参与国家自然科学基金课题研究和国家五类新药的开发;主持多项湖南省科技计划项目, 两获湖南省科学技术进步奖三等奖, 发表学术论文10余篇。E-mail:bingj82@126.com
基金资助:
国家自然科学基金资助项目(30901834); 教育部青年教师基金资助项目(20090162120023); 湖南省科技厅资助项目(2008FJ3130)

Role of ABCA4 in the mechanism and treatment of retinal degenerative diseases

JIANG Bing^1,2, ZHOU Hong-hao¹

¹Institute of Clinical Pharmacology Research, Central South University, Changsha 410078, Hunan, China;
²Department of Ophthalmology, the Second Xiang Ya Hospital of Central South University, Changsha 410011, Hunan, China

Received:2009-11-07 Revised:2009-11-07 Published:2020-10-26

摘要/Abstract

摘要： ABCA4 是三磷酸腺苷结合盒转运体亚家族ABCA 中的一员, 在脊椎动物的视锥和视杆细胞中表达。ABCA4, 又被称为辐射蛋白和ABCR,分为两个区域, 每个区域有跨膜区、糖基化胞外域和核苷酸结合结构域各一个。ABCA4 的基因编码区有超过500 个的突变, 这些突变与常染色体隐性遗传的视网膜退行性疾病谱相关, 包括Stargardt's 黄斑退变、视锥-视杆细胞营养不良和视网膜色素变性的一个亚型等。对ABCA4 的多项研究显示,ABCA4 的作用是作为视黄基磷脂酰乙醇胺的转运体, 在光激发后, 将光感受器上的有活性的视黄醛衍生物转运掉。通过对ABCA4 遗传和分子学的了解, 使得治疗Stargardt's 病和ABCA4相关的其他视网膜退行性疾病逐渐成为可能。

关键词: ABCA4, Stargardt's 病, 视锥-视杆细胞营养不良, 视网膜色素变性, 视网膜退行性疾病

Abstract: ABCA4 is a member of the ABCA subfamily of ATP binding cassette (ABC)transporters that is expressed in rod and cone photoreceptors of the vertebrate retina.ABCA4, also known as the Rim protein and ABCR, is organized as two tandem halves, each containing one transmembrane domain, one glyosylated extracellular domain and nucleotide-binding domain. Over 500 mutations in the gene encoding ABCA4 are associated with a spectrum of related autosomal recessive retinal degenerative diseases including Stargardt macular degeneration, cone-rod dystrophy and a subset of retinitis pigmentosa.Biochemical studies on the purified ABCA4 together with analysis of ABCA4 knockout mice and patients with Stragardt disease have implicated ABCA4 as a retinylidene-phosphatidylethanolamine transporter that facilitates the removal of potentially reactive retinal derivatives from photoreceptors following photoexcitation.Knowledge of the genetic and molecular basis for ABCA4 related retinal degenerative diseases is being used to develop rational therapeutic treatments for this set of disorders.

Key words: ABCA4, Stragardt's disease, conerod dystrophy, retinitis pigmentosa, retinal degenerative disease

中图分类号:

R968

江冰, 周宏灏. ABCA4 在视网膜退行性疾病中的作用及治疗[J]. 中国临床药理学与治疗学, 2009, 14(11): 1201-1207.

JIANG Bing, ZHOU Hong-hao. Role of ABCA4 in the mechanism and treatment of retinal degenerative diseases[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2009, 14(11): 1201-1207.

参考文献

[1] Allikmets R, Singh N, Sun H, et al.A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy[J].Nat Genet, 1997, 15(3):236-246.
[2] Nasonkin I, Illing M, KoehlerMR, et al.Mapping of the rod photoreceptor ABC transporter (ABCR)to 1p21-p22. 1 and identification of novel mutations in Stargardt's disease[J].Hum Genet, 1998, 102(1):21-26.
[3] Illing M, Molday LL, Molday RS.The 220-kDa rim protein of retinal rod outer segments is a member of the ABC transporter superfamily[J].J Biol Chem, 1997, 272(15):10303-10310.
[4] Papermaster DS, Schneider BG, Zorn MA, et al.Immunocytochemical localization of a large intrinsic membrane protein to the incisures and margins of frog rod outer segment disks[J].J Cell Biol, 1978, 78(2):415-425.
[5] Allikmets R, Shroyer NF, Singh N, et al.Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration[J].Science, 1997, 277(5333):1805-1807.
[6] Sun H, Nathans J.Stargardt's ABCR is localized to the disc membrane of retinal rod outer segments [letter][J]. Nat Genet, 1997, 17(1):15-16.
[7] Molday LL, Rabin AR, Molday RS.ABCR expression in foveal cone photoreceptors and its role in Stargardt macular dystrophy[J].Nat Genet, 2000, 25(3):257-258.
[8] Bhongsatiern J, Ohtsuki S, Tachikawa M, et al.Retinalspecific ATP-binding cassette transporter (ABCR ABCA4)is expressed at the choroids plexus in rat brain[J].J Neurochem, 2005, 92(5):1277-1280.
[9] Sun H, Nathans J.ABCR:rod photoreceptor-specific ABC transporter responsible for Stargardt disease[J]. Methods Enzymol, 2000, 315(4):879-897.
[10] vanMeer G, Halter D, Sprong H, et al.ABC lipid transporters: extruders, flippases, or flopless activators[J] ? FEBS Letters, 2006, 580(4):1171-1177.
[11] Sullivan JM.Focus on Molecules:ABCA4 (ABCR)-An import-directed photoreceptor retinoid flipase[J].Exp Eye Res, 2009, 89(5):602-603.
[12] Weng J, Mata NL, Azarian SM, et al.Insights into the function of Rim protein in photoreceptors and etiology of Stargardt's disease from the phenotype in abcr knockout mice[J].Cell, 1999, 98(1):13-23.
[13] Molday RS, Beharry S, Ahn J, et al.Binding of N-retinylidene- PE to ABCA4 and a model for its transport across membranes[J].Adv Exp Med Biol, 2006, 572:465-470.
[14] Maeda A, Maeda T, Golczak M, et al.Retinopathy in mice induced by disrupted all-trans-retinal clearance[J].J Biol Chem, 2008, 283(39):26684-26693.
[15] Mata NL, Weng J, Travis GH.Biosynthesis of a major lipofuscin fluorophore in mice and humans with ABCR-mediated retinal and macular degeneration[J].Proc Natl Acad Sci, 2000, 97(13):7154-7159.
[16] Mata NL, Tzekov RT, Liu X, et al.Delayed darkadaptation and lipofuscin accumulation in abcr + ? mice:implications for involvement of ABCR in age-related macular degeneration[J].Invest Ophthalmol Vis Sci, 2001, 42(8):1685-1690.
[17] Pawar AS, Qtaishat NM, Little DM, et al.Recovery of rod photoresponses in ABCR-deficient mice[J].Invest Ophthalmol Vis Sci, 2008, 49(6):2743-2755.
[18] Eldred GE, Lasky MR.Retinal age pigments generated by self-assembling lysosomotropic detergents[J].Nature, 1993, 361(6414):724-726.
[19] Shabat SB, Parish CA, Vollmer HR, et al.Biosynthetic studies of A2E, a major fluorophore of retinal pigment epithelial lipofuscin[J].J Biol Chem, 2002, 277(9):7183-7190.
[20] Sparrow JR, Boulton M.RPE lipofuscin and its role in retinal pathobiology[J].Exp Eye Res, 2005, 80(5):595-606.
[21] Sparrow JR, Nakanishi K, Parish CA.The lipofuscin fluorophore A2E mediates blue light-induced damage to retinal pigmented epithelial cells[J].Invest Ophthalmol Vis Sci, 2000, 41(7):1981-1989.
[22] Radu RA, Mata NL, Bagla A, et al.Light exposure stimulates formation of A2E oxiranes in a mouse model of Stargardt's macular degeneration[J].Proc Natl Acad Sci, 2004, 101(16):5928-5933.
[23] Kim SR, Jang YP, Jockusch S, et al.The all-transretinal dimer series of lipofuscin pigments in retinal pigment epithelial cells in a recessive Stargardt disease model[J]. Proc Natl Acad Sci, 2007, 104(49):19273-19278.
[24] Blacharski PA.Fundu flavimaculatus[M] D.A.Newsome (Ed.).Retinal Dystrophies and Degenerations.New York:Raven Press, 1988:135-159.
[25] Weleber RG.Stargardt's macular dystrophy[J].Arch Ophthalmol, 1994, 112(6):752-754.
[26] Fishman GA, Farbman JS, Alexander KR.Delayed rod dark adaptation in patients with Stargardt's disease[J]. Ophthalmology, 1991, 98(6):957-962.
[27] Lois N, Halfyard AS, Bird AC, et al.Fundus autofluorescence in Stargardt macular dystrophy-fundus flavimaculatus[J].Am J Ophthalmol, 2004, 138(1):55-63.
[28] Delori FC, Staurenghi G, Arend O, et al.In vivo measurement of lipofuscin in Stargardt's disease-Fundus flavimaculatus[J].Invest Ophthalmol Vis Sci, 1995, 36(11): 2327-2331.
[29] Cideciyan AV, Aleman TS, SwiderM, et al.Mutations in ABCA4 result in accumulation of lipofuscin before slowing of the retinoid cy cle:a reappraisal of the human disease sequence[J].Hum Mol Genet, 2004, 13(5):525-534.
[30] Noble KG, Carr RE.Stargardt's disease and fundus flavimaculatus[J].Arch Ophthalmol, 1979, 97(7):1281-1285.
[31] Gelisken O, De Laey JJ.A clinical review of Stargardt's disease and or fundus flavimaculatus with follow-up[J]. Int Ophthalmol, 1985, 8(4):225-235.
[32] Maugeri A, Klevering BJ, Rohrschneider K, et al.Mutations in the ABCA4 (ABCR)gene are the major cause of autosomal recessive cone-rod dystrophy[J].Am J Hum Genet, 2000, 67(4):960-966.
[33] Briggs CE, Rucinski D, Rosenfeld PJ, et al.Mutations in ABCR(ABCA4)in patients with Stargardt macular degeneration or cone-rod degeneration[J].Invest Ophthalmol Vis Sci, 2001, 42(10):2229-2236.
[34] Cremers FP, van de Pol DJ, van Driel M, et al.Autosomal recessive retinitis pigmentosa and cone-rod dystrophy caused by splice site mutations in the Stargardt's disease gene ABCR[J].Hum Mol Genet, 1998, 7(3):355-362.
[35] Martinez-Mir A, Paloma E, Allikmets R, et al.Retinitis pigmentosa caused by a homozygous mutation in the Stargardt disease gene ABCR[J].Nat Genet, 1998, 18(1): 11-12.
[36] Maugeri A, van Driel MA, van de Pol DJ, et al.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[J].Am J Hum Genet, 1999, 64(4): 1024-1035.
[37] van Driel MA, Maugeri A, Klevering BJ, et al.ABCR unites what ophthalmologists divide (s)[J].Ophthalmic Genet, 1998, 19(3):117-122.
[38] Shroyer NF, Lewis RA, Allikmets R, et al.The rod photoreceptor ATP-binding cassette transporter gene, ABCR, and retinal disease:from monogenic to multifactorial[J] Visi Res, 1999, 39(15):2537-2544.
[39] Cideciyan AV, Swider M, Aleman TS, et al.ABCA4 disease progression and a proposed strategy for gene therapy[J].Hum Mol Genet, 2009, 18(5):931-941.
[40] Wiszniewski W, Zaremba CM, Yatsenko AN, et al.ABCA4 mutations causing mislocalization are found frequently in patients with severe retinal dystrophies[J].Hum Mol Genet, 2005, 14(19):2769-2778.
[41] Pang JJ, Chang B, Kumar A, et al.Gene therapy restores vision-dependent behavior as well as retinal structure and function in a mouse model of RPE65 Leber congenital amaurosis[J].Mol Ther, 2006, 13(3):565-572.
[42] Min SH, Molday LL, Seeliger MW, et al.Prolonged recovery of retinal structure function after gene therapy in an Rs1h-deficient mouse model of x-linked juvenile retinoschisis[J].Mol Ther, 2005, 12(4):644-651.
[43] Kootstra NA, Verma IM.Gene therapy with viral vectors[J].Annu Rev Pharmacol Toxicol, 2003, 43:413-439.
[44] Allocca M, DoriaM, Petrillo M, et al.Serotype -dependent packaging of large genes in adeno-associated viral vectors results in effective gene delivery inmice[J].J Clin Invest, 2008, 118(5):1955-1964.
[45] Kong J, Kim SR, Binley K, et al.Correction of the disease phenotype in the mouse model of Stargardt disease by lentiviral gene therapy[J].Gene Ther, 2008, 15(19): 1311-1320.
[46] 刘昭前, 周宏灏.个体化药物治疗的新时代[J].中国临床药理学与治疗学, 2007, 12(1):1-6.
[47] 张伟, 贺毅憬, 周宏灏.遗传药理学的学科发展与未来[J].中国临床药理学与治疗学, 2008, 13(9): 961-965.
[48] Travis GH, GolczakM, Moise AR, et al.Diseases caused by defects in the visual cycle:retinoids as potential therapeutic agents[J].Annu Rev Pharmacol Toxicol, 2007, 47:469-512.
[49] Radu RA, Mata NL, Nusinowitz S, et al.Treatment with isotretinoin inhibits lipofuscin accumulation in amousemodel of recessive Stargardt's macular degeneration[J].Proc Natl Acad Sci, 2003, 100(8):4742-4747.
[50] Radu RA, Han Y, Bui TV, et al.Reductions in serum vitamin A arrest accumulation of toxic retinal fluorophores: a potential therapy for treatment of lipofuscin-based retinal diseases[J].Invest Ophthalmol Vis Sci, 2005, 46(12): 4393-4401.
[51] Golczak M, Kuksa V, Maeda T, et al.Positively charged retinoids are potent and selective inhibitors of the trans-cis isomerization in the retinoid (visual) cycle[J].Proc Natl Acad Sci, 2005, 102():23 8162-8167.

ABCA4 在视网膜退行性疾病中的作用及治疗

Role of ABCA4 in the mechanism and treatment of retinal degenerative diseases

PDF (PC)

可视化

被引次数

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 1

编辑推荐

Metrics

本文评价