Tamm Ernst R
Department of Anatomy, Molecular Anatomy and Embryology, University of Erlangen-Nürnberg, Universitätstr. 19, D-91054 Erlangen, Germany.
Prog Retin Eye Res. 2002 Jul;21(4):395-428. doi: 10.1016/s1350-9462(02)00010-1.
Mutations in the MYOC gene that encodes for myocilin are causative for some forms of juvenile and adult-onset primary open-angle glaucoma (POAG). Myocilin is a secreted 55-57kDa glycoprotein that forms dimers and multimers. Characteristic structural motifs include a myosin-like domain, a leucine zipper region and an olfactomedin domain. Most of the mutations that have been identified in patients with POAG are localized in the olfactomedin domain, which is highly conserved among species. In the eye, myocilin is expressed in high amounts in the trabecular meshwork (TM), sclera, ciliary body and iris, and at considerable lower amounts in retina and optic nerve head. Secreted myocilin is present in the aqueous humor. In the TM, myocilin is found within the cytoplasm of TM cells and in the juxtacanalicular region in association with fibrillar extracellular matrix components. Since patients with mutations in myocilin may have high intraocular pressures, the role of myocilin for aqueous humor outflow has been investigated and conflicting results have been obtained. Recombinant myocilin increases outflow resistance in perfused anterior segment organ cultures, while overexpression of myocilin after viral gene transfer appears to reduce outflow resistance. In TM cells, the expression of myocilin is induced upon treatment with dexamethasone at a time course similar to that observed in steroid-induced glaucoma. Other factors that induce myocilin expression are transforming growth factor-beta and mechanical stretch. Promoter elements that are important for the glucocorticoid induction have not been identified, but it has been shown that upstream stimulatory factor is critical for the basal promoter activity of MYOC. Mice with a targeted disruption of the myocilin gene do not express a phenotype, indicating that the glaucomatous phenotype in humans is not because of a loss-of-function effect. Experimental studies show that mutated myocilin is not secreted, but appears to accumulate in the cells. Such an accumulation might interfere with TM function and lead to impaired outflow resistance, but, so far, experimental evidence for such a scenario is lacking. In addition, the normal function(s) of myocilin is (are) still elusive.
编码肌纤蛋白的MYOC基因突变是某些形式的青少年和成人原发性开角型青光眼（POAG）的病因。肌纤蛋白是一种分泌型的55 - 57kDa糖蛋白，可形成二聚体和多聚体。其特征性结构基序包括一个肌球蛋白样结构域、一个亮氨酸拉链区域和一个嗅觉介质结构域。在POAG患者中鉴定出的大多数突变位于嗅觉介质结构域，该结构域在物种间高度保守。在眼睛中，肌纤蛋白在小梁网（TM）、巩膜、睫状体和虹膜中大量表达，而在视网膜和视神经头中的表达量则低得多。分泌的肌纤蛋白存在于房水中。在TM中，肌纤蛋白存在于TM细胞的细胞质中以及与纤维状细胞外基质成分相关的近小管区域。由于肌纤蛋白突变患者可能有高眼压，因此对肌纤蛋白在房水流出中的作用进行了研究，但结果相互矛盾。重组肌纤蛋白会增加灌注前房器官培养物中的流出阻力，而病毒基因转移后肌纤蛋白的过表达似乎会降低流出阻力。在TM细胞中，地塞米松处理后肌纤蛋白的表达在与类固醇诱导性青光眼相似的时间进程中被诱导。诱导肌纤蛋白表达的其他因素是转化生长因子-β和机械拉伸。尚未确定对糖皮质激素诱导重要的启动子元件，但已表明上游刺激因子对MYOC的基础启动子活性至关重要。肌纤蛋白基因靶向破坏的小鼠不表现出表型，这表明人类青光眼表型不是由于功能丧失效应。实验研究表明，突变的肌纤蛋白不分泌，而是似乎在细胞中积累。这种积累可能会干扰TM功能并导致流出阻力受损，但到目前为止，缺乏这种情况的实验证据。此外，肌纤蛋白的正常功能仍然难以捉摸。
