Overview of the Mutation Spectrum in Familial Exudative Vitreoretinopathy and Norrie Disease with Identification of 21 Novel Variants in FZD4, LRP5, and NDP
Overview of the Mutation Spectrum in Familial Exudative Vitreoretinopathy and Norrie Disease with Identification of 21 Novel Variants in FZD4, LRP5, and NDP
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DOI：
10.1002/humu.21250
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发表时间：
2010-06-01
期刊：
影响因子：
3.9
通讯作者：
Cremers, Frans P. M.
中科院分区：
文献类型：
--
作者：
Nikopoulos, Konstantinos;Venselaar, Hanka;Cremers, Frans P. M.
Wnt信号是细胞机制协调一系列生理过程的重要组成部分，如细胞存活、增殖和迁移。在Wilt信号所扮演的众多角色中，其规范分支调节眼睛器官发生和血管生成。编码低密度脂蛋白受体蛋白5 （LRP5）和卷曲蛋白4 （FZD4）的基因突变，作为Wnt配体的辅助受体，导致家族性渗出性玻璃体视网膜病变（FEVR）。此外，编码NDP（这些Wnt受体的配体）的基因突变会导致诺里病和出血热。FEVR和Norrie病具有相似的表型特征，包括周围视网膜血管化异常和眼部纤维血管团块的形成，可导致失明。在这篇突变更新中，我们报道了FZD4、LRP5和NDP的21个新变体，并讨论了错义突变可能的功能后果。此外，我们提供了上述基因中所有先前发表的变体的全面概述，并总结了携带同源基因突变的小鼠模型的表型特征。对与眼部发育和血液供应相关的Wnt信号的分子理解的增加，为准确的疾病诊断提供了更多的工具，这可能对治疗干预的发展很重要。[j], 2010。(C) 2010 Wiley-Liss, Inc。
Wnt signaling is a crucial component of the cell machinery orchestrating a series of physiological processes such as cell survival, proliferation, and migration. Among the plethora of roles that Wilt signaling plays, its canonical branch regulates eye organogenesis and angiogenesis. Mutations in the genes encoding the low density lipoprotein receptor protein 5 (LRP5) and frizzled 4 (FZD4), acting as coreceptors for Wnt ligands, cause familial exudative vitreoretinopathy (FEVR). Moreover, mutations in the gene encoding NDP, a ligand for these Wnt receptors, cause Norrie disease and FEVR. Both FEVR and Norrie disease share similar phenotypic characteristics, including abnormal vascularization of the peripheral retina and formation of fibrovascular masses in the eye that can lead to blindness. In this mutation update, we report 21 novel variants for FZD4, LRP5, and NDP, and discuss the putative functional consequences of missense mutations. In addition, we provide a comprehensive overview of all previously published variants in the aforementioned genes and summarize the phenotypic characteristics in mouse models carrying mutations in the orthologous genes. The increasing molecular understanding of Wnt signaling, related to ocular development and blood supply, offers more tools for accurate disease diagnosis that may be important in the development of therapeutic interventions. Hum Mutat 31:656-666, 2010. (C) 2010 Wiley-Liss, Inc.