Role of Factor H and Related Proteins in Regulating Complement Activation in the Macula, and Relevance to Age-Related Macular Degeneration.
Role of Factor H and Related Proteins in Regulating Complement Activation in the Macula, and Relevance to Age-Related Macular Degeneration.
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DOI：
10.3390/jcm4010018
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发表时间：
2015-01-01
影响因子：
3.9
通讯作者：
Bishop PN
中科院分区：
文献类型：
--
作者：
Clark SJ;Bishop PN
最近的革命在年龄相关性黄斑变性（AMD）遗传学已经证明，影响补体级联的替代途径的遗传改变对AMD的风险有重大影响。两个最重要的遗传基因座之一位于1号染色体上，包含编码补体因子H（FH）和因子H相关蛋白（FHR蛋白）的基因。在黄斑组织中，尤其是布鲁赫膜，存在相对高水平的FH截短剪接变体，称为因子H样蛋白1（FHL-1）。在这里，我们将讨论遗传变异如何改变这些蛋白质的数量，或通过改变它们的蛋白质序列，这些蛋白质的功能。特别是，常见的Y 402 H多态性影响FHL-1和FH定位于布鲁赫膜和脉络膜内层的能力，因为它改变了这些补体调节剂结合这些结构中硫酸乙酰肝素（HS）的能力。此外，存在来自布鲁赫膜的HS的年龄相关的损失。我们假设FHL-1和FH的402 H变体与布鲁赫膜的结合不良，加上由于年龄相关的HS损失导致的结合减少，最终导致FHL-1和FH与布鲁赫膜的结合不足。这可能导致补体激活、炎症，从而易患AMD。
The recent revolution in age-related macular degeneration (AMD) genetics has demonstrated that genetic alterations affecting the alternative pathway of the complement cascade have a major influence on AMD risk. One of the two most important genetic loci is on chromosome 1 and contains genes encoding complement factor H (FH) and the factor H related proteins (FHR proteins). In macular tissue, especially Bruch’s membrane, relatively high levels of a truncated splice variant of FH called factor H-like protein 1 (FHL-1) are present. Here we discuss how genetic variations may alter the amounts, or by altering their protein sequences, the functions of these proteins. In particular, the common Y402H polymorphism affects the ability of FHL-1 and FH to localize to Bruch’s membrane and the inner choroid because it alters the ability of these complement regulators to bind heparan sulphate (HS) in these structures. In addition, there is an age-related loss of HS from Bruch’s membrane. We hypothesize that a combination of poor binding of the 402H variants of FHL-1 and FH to Bruch’s membrane, combined with a decrease in binding due to age-related HS loss, eventually results in insufficient FHL-1 and FH binding to Bruch’s membrane. This could result in complement activation, inflammation and thereby predispose to AMD.
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影响因子：
3.5
作者：
Ansari M;McKeigue PM;Skerka C;Hayward C;Rudan I;Vitart V;Polasek O;Armbrecht AM;Yates JR;Vatavuk Z;Bencic G;Kolcic I;Oostra BA;Van Duijn CM;Campbell S;Stanton CM;Huffman J;Shu X;Khan JC;Shahid H;Harding SP;Bishop PN;Deary IJ;Moore AT;Dhillon B;Rudan P;Zipfel PF;Sim RB;Hastie ND;Campbell H;Wright AF
通讯作者：
Wright AF
DOI：
10.1073/pnas.0501536102
发表时间：
2005-05-17
影响因子：
11.1
作者：
Hageman, GS;Anderson, DH;Allikmets, R
通讯作者：
Allikmets, R
影响因子：
3.5
作者：
Hecker, Laura A.;Edwards, Albert O.;Oppermann, Martin
通讯作者：
Oppermann, Martin
DOI：
10.4049/jimmunol.1401613
发表时间：
2014-11-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Clark SJ;Schmidt CQ;White AM;Hakobyan S;Morgan BP;Bishop PN
通讯作者：
Bishop PN
影响因子：
30.8
作者：
Fritsche, Lars G.;Chen, Wei;Schu, Matthew;Yaspan, Brian L.;Yu, Yi;Thorleifsson, Gudmar;Zack, Donald J.;Arakawa, Satoshi;Cipriani, Valentina;Ripke, Stephan;Igo, Robert P., Jr.;Buitendijk, Gabrielle H. S.;Sim, Xueling;Weeks, Daniel E.;Guymer, Robyn H.;Merriam, Joanna E.;Francis, Peter J.;Hannum, Gregory;Agarwal, Anita;Armbrecht, Ana Maria;Audo, Isabelle;Aung, Tin;Barile, Gaetano R.;Benchaboune, Mustapha;Bird, Alan C.;Bishop, Paul N.;Branham, Kari E.;Brooks, Matthew;Brucker, Alexander J.;Cade, William H.;Cain, Melinda S.;Campochiaroll, Peter A.;Chan, Chi-Chao;Cheng, Ching-Yu;Chew, Emily Y.;Chin, Kimberly A.;Chowers, Itay;Clayton, David G.;Cojocaru, Radu;Conley, Yvette P.;Cornes, Belinda K.;Daly, Mark J.;Dhillon, Baljean;Edwards, Albert;Evangelou, Evangelos;Fagemess, Jesen;Ferreyra, Henry A.;Friedman, James S.;Geirsdottir, Asbjorg;George, Ronnie J.;Gieger, Christian;Gupta, Neel;Hagstrom, Stephanie A.;Harding, Simon P.;Haritoglou, Christos;Heckenlively, John R.;Hoz, Frank G.;Hughes, Guy;Ioannidis, John P. A.;Ishibashi, Tatsuro;Joseph, Peronne;Jun, Gyungah;Kamatani, Yoichiro;Katsanis, Nicholas;Keilhauer, Claudia N.;Khan, Jane C.;Kim, Ivana K.;Kiyohara, Yutaka;Klein, Barbara E. K.;Klein, Ronald;Kovach, Jaclyn L.;Kozak, Igor;Lee, Clara J.;Lee, Kristine E.;Lichtner, Peter;Lotery, Andrew J.;Meitinger, Thomas;Mitchell, Paul;Mohand-Saied, Saddek;Moore, Anthony T.;Morgan, Denise J.;Morrison, Margaux A.;Myers, Chelsea E.;Naj, Adam C.;Nakamura, Yusuke;Okada, Yukinori;Orlin, Anton;Ortube, M. Carolina;Othman, Mohammad I.;Pappas, Chris;Park, Kyu Hyung;Pauer, Gayle J. T.;Peachey, Neal S.;Poch, Olivier;Priya, Rinki Ratna;Reynolds, Robyn;Richardson, Andrea J.;Ripp, Raymond;Rudolph, Guenther;Ryu, Euijung;Sahel, Jose-Alain;Schaumberg, Debra A.;Scholl, Hendrik P. N.;Schwartz, Stephen G.;Scott, William K.;Shahid, Humma;Sigurdsson, Haraldur;Silvestri, Giuliana;Sivakumaran, Theru A.;Smith, R. Theodore;Sobrin, Lucia;Souied, Eric H.;Stambolian, Dwight E.;Stefansson, Hreinn;Sturgill-Short, Gwen M.;Takahashi, Atsushi;Tosakulwong, Nirubol;Truitt, Barbara J.;Tsironi, Evangelia E.;Uitterlinden, Andre G.;van Duijn, Cornelia M.;Vijaya, Lingam;Vingerling, Johannes R.;Vithana, Eranga N.;Webster, Andrew R.;Wichmann, H-Erich;Winkler, Thomas W.;Wong, Tien Y.;Wright, Alan F.;Zelenika, Diana;Zhang, Ming;Zhao, Ling;Zhang, Kang;Klein, Michael L.;Hageman, Gregory S.;Lathrop, G. Mark;Stefansson, Kari;Allikmets, Rando;Baird, Paul N.;Gorin, Michael B.;Wang, Jie Jin;Klaver, Caroline C. W.;Seddon, Johanna M.;Pericak-Vance, Margaret A.;Iyengar, Sudha K.;Yates, John R. W.;Swaroop, Anand;Weber, Bernhard H. F.;Kubo, Michiaki;DeAngelis, Margaret M.;Leveillard, Thierry;Thorsteinsdottir, Unnur;Haines, Jonathan L.;Farrer, Lindsay A.;Heid, Iris M.;Abecasis, Goncalo R.
通讯作者：
Abecasis, Goncalo R.