Interaction of complement factor h and fibulin3 in age-related macular degeneration.
Interaction of complement factor h and fibulin3 in age-related macular degeneration.
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DOI：
10.1371/journal.pone.0068088
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Wistow G
中科院分区：
文献类型：
--
作者：
Wyatt MK;Tsai JY;Mishra S;Campos M;Jaworski C;Fariss RN;Bernstein SL;Wistow G
年龄相关性黄斑变性（AMD）是视力丧失的主要原因。它与视网膜色素上皮 (RPE) 基底膜中特征性斑块状沉积物（软玻璃膜疣）的形成有关。补体因子 H (CFH) 的短共有重复结构域 7 (SCR7) 中的序列变异 (Y402H) 与“干性”AMD 风险相关。我们询问这种疾病的眼睛靶向是否可能与 CFH SCR7 与衰老人类 RPE/脉络膜中表达的蛋白质的特定相互作用有关，这种相互作用可能有助于玻璃疣中的蛋白质沉积。使用 CFH SCR7 诱饵对来自老年供体的视网膜色素上皮/脉络膜库进行酵母 2 杂交 (Y2H) 筛选，检测到与 EFEMP1/Fibulin 3 (Fib3) 的相互作用，EFEMP1/Fibulin 3 (Fib3) 是遗传性黄斑变性的基因座，并且在 AMD 中也会累积基底至黄斑 RPE。 CFH/Fib3 相互作用通过天然蛋白的免疫共沉淀得到验证。使用不同重组蛋白构建体进行的定量 Y2H 和 ELISA 检测均证明 Fib3 对疾病相关的 CFH 402H 变体具有更高的亲和力。免疫标记显示，CFH 402H (H/H) 纯合子的两名 AMD 供体的软玻璃疣中富含胆固醇的结构域内的球状沉积物中 CFH 和 Fib3 共定位。这种标记模式与具有 Y/Y 和 H/Y 基因型的眼睛示例中看到的标记模式非常不同。 CFH 402H/Fib3 相互作用可能有助于某些患者软玻璃膜疣病理聚集的发展，因此可能为某些形式的 AMD 提供治疗干预的目标。
Age-related macular degeneration (AMD) is a major cause of vision loss. It is associated with development of characteristic plaque-like deposits (soft drusen) in Bruch’s membrane basal to the retinal pigment epithelium (RPE). A sequence variant (Y402H) in short consensus repeat domain 7 (SCR7) of complement factor H (CFH) is associated with risk for “dry” AMD. We asked whether the eye-targeting of this disease might be related to specific interactions of CFH SCR7 with proteins expressed in the aging human RPE/choroid that could contribute to protein deposition in drusen. Yeast 2-hybrid (Y2H) screens of a retinal pigment epithelium/choroid library derived from aged donors using CFH SCR7 baits detected an interaction with EFEMP1/Fibulin 3 (Fib3), which is the locus for an inherited macular degeneration and also accumulates basal to macular RPE in AMD. The CFH/Fib3 interaction was validated by co-immunoprecipitation of native proteins. Quantitative Y2H and ELISA assays with different recombinant protein constructs both demonstrated higher affinity for Fib3 for the disease-related CFH 402H variant. Immuno-labeling revealed colocalization of CFH and Fib3 in globular deposits within cholesterol-rich domains in soft drusen in two AMD donors homozygous for CFH 402H (H/H). This pattern of labeling was quite distinct from those seen in examples of eyes with Y/Y and H/Y genotypes. The CFH 402H/Fib3 interaction could contribute to the development of pathological aggregates in soft drusen in some patients and as such might provide a target for therapeutic intervention in some forms of AMD.
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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
DOI：
10.1073/pnas.222551899
发表时间：
2002-11-12
影响因子：
11.1
作者：
Crabb, JW;Miyagi, M;Hollyfield, JG
通讯作者：
Hollyfield, JG
DOI：
10.1136/bjophthalmol-2011-300344
发表时间：
2011-12
期刊：
The British journal of ophthalmology
影响因子：
--
作者：
Curcio CA;Johnson M;Rudolf M;Huang JD
通讯作者：
Huang JD
影响因子：
56.9
作者：
Edwards, AO;Ritter, R;Farrer, LA
通讯作者：
Farrer, LA
影响因子：
30.8
作者：
Hughes, Anne E.;Orr, Nick;Chakravarthy, Usha
通讯作者：
Chakravarthy, Usha