Mutations in zebrafish lrp2 result in adult-onset ocular pathogenesis that models myopia and other risk factors for glaucoma.
Mutations in zebrafish lrp2 result in adult-onset ocular pathogenesis that models myopia and other risk factors for glaucoma.
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DOI：
10.1371/journal.pgen.1001310
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发表时间：
2011-02
期刊：
影响因子：
4.5
通讯作者：
Link BA
中科院分区：
文献类型：
--
作者：
Veth KN;Willer JR;Collery RF;Gray MP;Willer GB;Wagner DS;Mullins MC;Udvadia AJ;Smith RS;John SW;Gregg RG;Link BA
青光眼包括一组基因复杂的视网膜神经疾病，通常发生在晚年，以视神经头进行性病理和视网膜神经节细胞变性为特征。除年龄和家族史外，青光眼的其他重要危险因素包括高眼压和近视。青光眼的复杂性使得在动物身上建立模型变得困难，但识别相关基因也是一项挑战。我们使用斑马鱼来鉴定一种遗传复杂的隐性突变，该突变显示了青光眼的危险因素，包括成人发作的严重近视、高眼压和进行性视网膜神经节细胞病理。对一个非互补等位基因的定位克隆和分析表明，低密度脂蛋白受体相关蛋白2(LRP2)的无义突变是突变表型的基础。Lrp2，以前称为megalin，是一种内吞受体，可与多种生物活性分子结合，包括Sonic hedgehog、骨形态发生蛋白4、视黄醇结合蛋白、维生素D结合蛋白和载脂蛋白E等。详细的表型分析表明，随着lrp2突变鱼年龄的增长，许多人--但不是所有人--会患上高眼压和严重近视，并伴有明显增大的眼球。这会导致视网膜拉伸和对视网膜神经节细胞的长期应激，最终显示出发病迹象。我们的研究表明，Lrp2介导的动态平衡改变对近视和人类青光眼的其他危险因素具有重要作用，并为进一步研究与这种疾病相关的表型建立了一个新的遗传模型。复杂的遗传遗传，包括不同的外显率和严重程度，是许多常见眼病的基础。在这项研究中，我们提出了对斑马鱼突变体Bugeye的分析，该突变体显示了多种眼部表型的复杂遗传，这些表型是青光眼的已知危险因素，包括高度近视、高眼压和视网膜神经节细胞中应激反应基因的上调。分子遗传学分析显示，低密度脂蛋白受体相关蛋白2(LRP2)的突变是突变表型的基础。Lrp2是一种在眼上皮细胞中表达的大型跨膜蛋白。它通过受体介导的内吞作用促进多种分泌的生物活性因子的转运和清除。青光眼是一种进行性失明疾病，通常出现在成年期，其特征是视神经受损，继而出现神经节细胞死亡。在Bugeye/lrp2突变体中，神经节细胞死亡显著增加，但出人意料地温和，因此他们没有模拟青光眼的这一终点。因此，Bugeye/lrp2突变可以被认为是一种有价值的遗传模型，可用于(A)眼炎、近视和调节眼生长；(B)识别改变所观察到的眼表型的基因和途径；以及(C)在高度近视和眼压升高的背景下研究视网膜神经节细胞病理的启动。
The glaucomas comprise a genetically complex group of retinal neuropathies that typically occur late in life and are characterized by progressive pathology of the optic nerve head and degeneration of retinal ganglion cells. In addition to age and family history, other significant risk factors for glaucoma include elevated intraocular pressure (IOP) and myopia. The complexity of glaucoma has made it difficult to model in animals, but also challenging to identify responsible genes. We have used zebrafish to identify a genetically complex, recessive mutant that shows risk factors for glaucoma including adult onset severe myopia, elevated IOP, and progressive retinal ganglion cell pathology. Positional cloning and analysis of a non-complementing allele indicated that non-sense mutations in low density lipoprotein receptor-related protein 2 (lrp2) underlie the mutant phenotype. Lrp2, previously named Megalin, functions as an endocytic receptor for a wide-variety of bioactive molecules including Sonic hedgehog, Bone morphogenic protein 4, retinol-binding protein, vitamin D-binding protein, and apolipoprotein E, among others. Detailed phenotype analyses indicated that as lrp2 mutant fish age, many individuals—but not all—develop high IOP and severe myopia with obviously enlarged eye globes. This results in retinal stretch and prolonged stress to retinal ganglion cells, which ultimately show signs of pathogenesis. Our studies implicate altered Lrp2-mediated homeostasis as important for myopia and other risk factors for glaucoma in humans and establish a new genetic model for further study of phenotypes associated with this disease. Complex genetic inheritance, including variable penetrance and severity, underlies many common eye diseases. In this study, we present analysis of a zebrafish mutant, bugeye, which shows complex inheritance of multiple ocular phenotypes that are known risk factors for glaucoma, including high myopia, elevated intraocular pressure, and up-regulation of stress-response genes in retinal ganglion cells. Molecular genetic analysis revealed that mutations in low density lipoprotein receptor-related protein 2 (lrp2) underlie the mutant phenotypes. Lrp2 is a large transmembrane protein expressed in epithelia of the eye. It facilitates transport and clearance of multiple secreted bioactive factors through receptor-mediated endocytosis. Glaucoma, a progressive blinding disorder, usually presents in adulthood and is characterized by optic nerve damage followed by ganglion cell death. In bugeye/lrp2 mutants, ganglion cell death was significantly elevated, but surprisingly moderate, and therefore they do not model this endpoint of glaucoma. As such, bugeye/lrp2 mutants should be considered valuable as a genetic model (A) for buphthalmia, myopia, and regulated eye growth; (B) for identifying genes and pathways that modify the observed ocular phenotypes; and (C) for studying the initiation of retinal ganglion cell pathology in the context of high myopia and elevated intraocular pressure.
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影响因子：
1.8
作者：
CHARMAN, WN;TUCKER, J
通讯作者：
TUCKER, J
DOI：
10.1002/ajmg.1320470518
发表时间：
1993-10-01
期刊：
AMERICAN JOURNAL OF MEDICAL GENETICS
影响因子：
--
作者：
DONNAI, D;BARROW, M
通讯作者：
BARROW, M
影响因子：
6.2
作者：
DABIN, I;BARNSTABLE, CJ
通讯作者：
BARNSTABLE, CJ
影响因子：
16.2
作者：
DOSTER, SK;LOZANO, AM;WILLARD, MB
通讯作者：
WILLARD, MB
DOI：
10.1002/neu.480240410
发表时间：
1993-04-01
期刊：
JOURNAL OF NEUROBIOLOGY
影响因子：
--
作者：
HERDEGEN, T;BASTMEYER, M;ZIMMERMANN, M
通讯作者：
ZIMMERMANN, M