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
Human Genetics Division, University of Southampton, Southampton, Hampshire, United Kingdom.
Hum Mutat. 2006 Jun;27(6):568-74. doi: 10.1002/humu.20344.
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.
年龄相关性黄斑变性（ARMD）是西方世界不可逆视力丧失的主要原因，全球约有2500万人受其影响。其发病机制复杂，且已有报道称FBLN5中的错义突变与ARMD有关。我们通过完成第一项关于ARMD中FBLN5基因的欧洲研究（使用两个欧洲队列，共805例ARMD患者和279例对照），并确定错义突变对纤连蛋白5表达的功能影响，来研究纤连蛋白5在ARMD中的作用。我们还将FBLN5基因型与ARMD表型进行了关联分析。我们在ARMD患者中发现了两个对照中不存在的新序列变化，并表达了这些变化以及其他九个与ARMD相关的已报道的FBLN5突变和两个与常染色体隐性疾病皮肤松弛症相关的突变。对于四个ARMD（p.G412E、p.G267S、p.I169T和p.Q124P）和两个皮肤松弛症（p.S227P、p.C217R）突变，纤连蛋白5的分泌显著减少（P<0.001）。这些结果表明，一些与ARMD相关的错义突变会导致纤连蛋白5分泌减少，可能相应地减少弹性蛋白生成。本研究证实了之前确定FBLN5突变与ARMD之间存在关联的工作，并首次提出了这些突变可导致ARMD的功能机制。它进一步证明FBLN5突变可与ARMD的不同表型相关（不限于先前描述的表皮玻璃膜疣类型）。这些知识最终可能会促成针对这种常见疾病的新疗法的开发。
