Reduced secretion of fibulin 5 in age-related macular degeneration and cutis laxa.
Reduced secretion of fibulin 5 in age-related macular degeneration and cutis laxa.
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DOI：
10.1002/humu.20344
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发表时间：
2006-06
期刊：
影响因子：
3.9
通讯作者：
Trump, Dorothy
中科院分区：
文献类型：
--
作者：
Lotery, Andrew J;Baas, Dominique;Ridley, Caroline;Jones, Richard P O;Klaver, Caroline C W;Stone, Edwin;Nakamura, Tomoyuki;Luff, Andrew;Griffiths, Helen;Wang, Tao;Bergen, Arthur A B;Trump, Dorothy
视网膜相关性黄斑变性（ARMD）是西方世界不可逆视力丧失的主要原因，影响全球约2500万人。发病机制是复杂的，FBLN5中的错义突变已被报道与ARMD相关。我们已经调查了fibulin 5在ARMD中的作用，完成了第一个欧洲研究FBLN5基因在ARMD中的作用（使用2个欧洲队列的805名ARMD患者和279名对照），并通过确定错义突变对fibulin 5表达的功能影响。我们还将FBLN5基因型与ARMD表型相关联。我们在ARMD患者中发现了两个新的序列变化，这些变化在对照组中不存在，并表达了这些变化和其他9个与ARMD相关的FBLN5突变以及2个与常染色体隐性遗传病皮肤拉克萨相关的突变。对于四种ARMD（p.G412E、p.G267S、p.I169T和p.Q124P）和两种皮肤松弛（p.S227P、p.C217R）突变，纤蛋白5分泌显著降低（P<0.001）。这些结果表明，与ARMD相关的一些错义突变导致fibulin 5分泌减少，弹性蛋白生成可能相应减少。这项研究证实了先前的工作，确定了FBLN5突变与ARMD之间的关联，并首次提出了这些突变可能导致ARMD的功能机制。它进一步证明FBLN5突变可以与ARMD的不同表型（不限于先前描述的表皮玻璃疣类型）相关。这些知识可能最终导致这种常见疾病的新疗法的发展。
Age-related macular degeneration (ARMD) is the leading cause of irreversible visual loss in the Western world, affecting approximately 25 million people worldwide. The pathogenesis is complex and missense mutations in FBLN5 have been reported in association with ARMD. We have investigated the role of fibulin 5 in ARMD by completing the first European study of the gene FBLN5 in ARMD (using 2 European cohorts of 805 ARMD patients and 279 controls) and by determining the functional effects of the missense mutations on fibulin 5 expression. We also correlated the FBLN5 genotype with the ARMD phenotype. We found two novel sequence changes in ARMD patients that were absent in controls and expressed these and the other nine reported FBLN5 mutations associated with ARMD and two associated with the autosomal recessive disease cutis laxa. Fibulin 5 secretion was significantly reduced (P<0.001) for four ARMD (p.G412E, p.G267S, p.I169 T, and p.Q124P) and two cutis laxa (p.S227P, p.C217R) mutations. These results suggest that some missense mutations associated with ARMD lead to decreased fibulin 5 secretion with a possible corresponding reduction in elastinogenesis. This study confirms the previous work identifying an association between FBLN5 mutations and ARMD and for the first time suggests a functional mechanism by which these mutations can lead to ARMD. It further demonstrates that FBLN5 mutations can be associated with different phenotypes of ARMD (not limited to the previously described cuticular drusen type). Such knowledge may ultimately lead to the development of novel therapies for this common disease.