Functional analysis of LOXL1 gene polymorphisms in the pathogenesis of pseudoexfoliation syndrome/glaucoma

LOXL1基因多态性在假性剥脱综合征/青光眼发病机制中的功能分析

• 批准号: 226809164
• 负责人: Professorin Dr. Ursula Schlötzer-Schrehardt
• 金额: --
• 依托单位: Augenklinik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/226809164?language=en
• 关键词: Functional; analysis; LOXL1; gene; polymorphisms

Pseudoexfoliation (PEX) syndrome, one of the most frequent causes of chronic open-angle glaucoma, represents a genetically determined, fibrotic matrix process, which leads to progressive accumulation of an abnormal elastotic material in intra- and extraocular tissues. Genetic studies identified a highly significant association between two coding and several non-coding polymorphisms in the LOXL1 gene on chromosome 15q24.1 with PEX syndrome and PEX glaucoma. Since these LOXL1 risk variants were found to occur in almost 100% of PEX patients in all geographical populations worldwide, LOXL1 appears to represent a major risk factor which is absolutely necessary, though not sufficient, for manifestation of the PEX phenotype. In view of the key role of LOXL1 (lysyl oxidase-like 1) in elastogenesis, the working hypothesis of this research project postulates that the PEX-associated LOXL1 risk variants are essentially involved in the pathogenesis of the elastotic PEX process through functional and/or regulatory effects. The growth factor TGF-ß1, which is considered a central mediator of the fibrotic PEX process and a key regulator of lysyl oxidase expression and activity, may act as a comodulating external factor. On the basis of substantial preliminary work on establishing stable LOXL1-expression systems in HEK193 cells, E.coli bacteria, and primary human fibroblasts, the aims of this project include: 1) a comparative functional characterization of the recombinantly expressed LOXL1 missense variants with regard to expression, secretion, processing, catalytic activity, protein interactions, and substrate binding properties; 2) a comparative analysis of the effect of the LOXL1 missense variants on extracellular matrix synthesis and assembly and 3) on the TGF-ß1 signal transduction in a fibroblast cell culture model in vitro; and 4) a comparative analysis of the effect of the non-coding LOXL1 variants on the regulation of LOXL1 expression. These functional analyses will not only increase our understanding of the molecular pathomechanisms underlying the fibrotic PEX process, but may also open up new rational therapeutic strategies for one of the most frequent causes of glaucoma.

假性剥脱综合征是慢性开角型青光眼最常见的病因之一，表现为一种由基因决定的纤维化基质过程，导致异常弹力物质在眼内外组织中的进行性积聚。遗传学研究发现，染色体15q24.1上LOXL1基因的两个编码和几个非编码多态与PEX综合征和PEX青光眼存在高度显著的相关性。由于这些LOXL1风险变异被发现发生在全世界几乎100%的PEX患者中，LOXL1似乎代表着一个主要的危险因素，对于PEX表型的表现来说，LOXL1似乎是绝对必要的，尽管不是充分的。鉴于LOXL1(赖氨酰氧化酶样1)在弹性发生中的关键作用，本研究项目的工作假说假设与PEX相关的LOXL1风险变异体主要通过功能和/或调节效应参与弹性PEX过程的发病。生长因子转化生长因子β1被认为是纤维化PEX过程的中心调节因子，也是赖氨酰氧化酶表达和活性的关键调节因子，它可能起到协同调节外部因子的作用。在HEK193细胞、大肠杆菌和原代人成纤维细胞中建立稳定的LOXL1表达系统的大量前期工作的基础上，本项目的目标包括：1)比较重组表达的LOXL1错义变体在表达、分泌、加工、催化活性、蛋白质相互作用和底物结合特性方面的功能特性；2)比较分析LOXL1错义变体对细胞外基质合成和组装的影响；3)在体外成纤维细胞培养模型中对转化生长因子-β1信号转导的影响；以及4)比较分析非编码LOXL1变体对LOXL1表达调控的影响。这些功能分析不仅将增加我们对纤维化PEX过程背后的分子病理机制的了解，而且还可能为青光眼的最常见原因之一开辟新的合理治疗策略。

项目成果

Expression and regulation of LOXL1 and elastin-related genes in eyes with exfoliation syndrome.

• DOI: 10.1097/ijg.0000000000000120
• 发表时间: 2014-10-01
• 期刊: Journal of glaucoma
• 影响因子: 2
• 作者: Zenkel, Matthias;Schlotzer-Schrehardt, Ursula
• 通讯作者: Schlotzer-Schrehardt, Ursula

The composition of exfoliation material and the cells involved in its production.

去角质材料的成分和参与其生产的细胞

• DOI: 10.1097/ijg.0000000000000123
• 发表时间: 2014
• 期刊: Journal of glaucoma
• 影响因子: 2
• 作者: Zenkel M;Schlötzer-Schrehardt U
• 通讯作者: Schlötzer-Schrehardt U

A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome.

• DOI: 10.1038/ng.3226
• 发表时间: 2015-04
• 期刊: Nature genetics
• 影响因子: 30.8
• 作者: Aung T;Ozaki M;Mizoguchi T;Allingham RR;Li Z;Haripriya A;Nakano S;Uebe S;Harder JM;Chan AS;Lee MC;Burdon KP;Astakhov YS;Abu-Amero KK;Zenteno JC;Nilgün Y;Zarnowski T;Pakravan M;Safieh LA;Jia L;Wang YX;Williams S;Paoli D;Schlottmann PG;Huang L;Sim KS;Foo JN;Nakano M;Ikeda Y;Kumar RS;Ueno M;Manabe S;Hayashi K;Kazama S;Ideta R;Mori Y;Miyata K;Sugiyama K;Higashide T;Chihara E;Inoue K;Ishiko S;Yoshida A;Yanagi M;Kiuchi Y;Aihara M;Ohashi T;Sakurai T;Sugimoto T;Chuman H;Matsuda F;Yamashiro K;Gotoh N;Miyake M;Astakhov SY;Osman EA;Al-Obeidan SA;Owaidhah O;Al-Jasim L;Al Shahwan S;Fogarty RA;Leo P;Yetkin Y;Oğuz Ç;Kanavi MR;Beni AN;Yazdani S;Akopov EL;Toh KY;Howell GR;Orr AC;Goh Y;Meah WY;Peh SQ;Kosior-Jarecka E;Lukasik U;Krumbiegel M;Vithana EN;Wong TY;Liu Y;Koch AE;Challa P;Rautenbach RM;Mackey DA;Hewitt AW;Mitchell P;Wang JJ;Ziskind A;Carmichael T;Ramakrishnan R;Narendran K;Venkatesh R;Vijayan S;Zhao P;Chen X;Guadarrama-Vallejo D;Cheng CY;Perera SA;Husain R;Ho SL;Welge-Luessen UC;Mardin C;Schloetzer-Schrehardt U;Hillmer AM;Herms S;Moebus S;Nöthen MM;Weisschuh N;Shetty R;Ghosh A;Teo YY;Brown MA;Lischinsky I;Blue Mountains Eye Study GWAS Team;Wellcome Trust Case Control Consortium 2;Crowston JG;Coote M;Zhao B;Sang J;Zhang N;You Q;Vysochinskaya V;Founti P;Chatzikyriakidou A;Lambropoulos A;Anastasopoulos E;Coleman AL;Wilson MR;Rhee DJ;Kang JH;May-Bolchakova I;Heegaard S;Mori K;Alward WL;Jonas JB;Xu L;Liebmann JM;Chowbay B;Schaeffeler E;Schwab M;Lerner F;Wang N;Yang Z;Frezzotti P;Kinoshita S;Fingert JH;Inatani M;Tashiro K;Reis A;Edward DP;Pasquale LR;Kubota T;Wiggs JL;Pasutto F;Topouzis F;Dubina M;Craig JE;Yoshimura N;Sundaresan P;John SW;Ritch R;Hauser MA;Khor CC
• 通讯作者: Khor CC