Rare protective variants and glaucoma-relevant cell stressors modulate Angiopoietin-like 7 expression

被引:4
作者
Aboobakar, Inas F. [1 ]
Collantes, Edward Ryan A. [1 ]
Hauser, Michael A. [2 ]
Stamer, W. Daniel [2 ,3 ]
Wiggs, Janey L. [1 ]
机构
[1] Harvard Med Sch, Massachusetts Eye & Ear, Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA
[2] Duke Univ, Sch Med, Dept Ophthalmol, Durham, NC 27710 USA
[3] Duke Univ, Sch Med, Dept Biomed Engn, Durham, NC 27710 USA
基金
美国国家卫生研究院;
关键词
TRABECULAR MESHWORK CELLS; PRIMARY OPEN-ANGLE; INTRAOCULAR-PRESSURE; ENDOTHELIAL-CELLS; PROTEINS; GENE; ACCUMULATION; DYSFUNCTION; INDUCTION; SECRETION;
D O I
10.1093/hmg/ddad083
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Rare missense and nonsense variants in the Angiopoietin-like 7 (ANGPTL7) gene confer protection from primary open-angle glaucoma (POAG), though the functional mechanism remains uncharacterized. Interestingly, a larger variant effect size strongly correlates with in silico predictions of increased protein instability (r = -0.98), suggesting that protective variants lower ANGPTL7 protein levels. Here, we show that missense and nonsense variants cause aggregation of mutant ANGPTL7 protein in the endoplasmic reticulum (ER) and decreased levels of secreted protein in human trabecular meshwork (TM) cells; a lower secreted:intracellular protein ratio strongly correlates with variant effects on intraocular pressure (r = 0.81). Importantly, accumulation of mutant protein in the ER does not increase expression of ER stress proteins in TM cells (P > 0.05 for all variants tested). Cyclic mechanical stress, a glaucoma-relevant physiologic stressor, also significantly lowers ANGPTL7 expression in primary cultures of human Schlemm's canal (SC) cells (-2.4-fold-change, P = 0.01). Collectively, these data suggest that the protective effects of ANGPTL7 variants in POAG stem from lower levels of secreted protein, which may modulate responses to physiologic and pathologic ocular cell stressors. Downregulation of ANGPTL7 expression may therefore serve as a viable preventative and therapeutic strategy for this common, blinding disease.
引用
收藏
页码:2523 / 2531
页数:9
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