Siggs Owen M, Souzeau Emmanuelle, Craig Jamie E
a Department of Ophthalmology , Flinders University, Flinders Medical Centre , Adelaide , Australia.
Ophthalmic Genet. 2019 Feb;40(1):12-16. doi: 10.1080/13816810.2018.1561904. Epub 2019 Jan 2.
Stability of the crystalline lens requires formation of microfibril bundles and their higher-order structures of ciliary zonules. Trauma, malformation, or degeneration of the ciliary zonules can lead to dislocation or displacement of the lens, which in turn can cause transient or permanent loss of visual acuity. The purpose of this study was to identify the predicted substrates of aspartyl/asparaginyl hydroxylase (ASPH), a 2-oxoglutarate- and Fe-dependent hydroxylase, which may account for the lens instability phenotype of ASPH-associated syndromes.
A single proband of European ancestry with spherophakia and high myopia was subjected to exome sequencing. Proteins containing the ASPH hydroxylation motif were identified within the SwissProt protein database.
We identified 105 putative substrates of ASPH-mediated hydroxylation in the human proteome, of which two (fibrillin-1 and latent transforming growth factor beta binding protein-2) are associated with inherited ectopia lentis syndromes, and are essential for microfibril and ciliary zonule development.
Our results implicate ASPH-mediated hydroxylation in the formation of FBN1/LTBP2 microfibril bundles and competent ciliary zonules.
晶状体的稳定性需要睫状小带微原纤维束及其高阶结构的形成。睫状小带的创伤、畸形或退化可导致晶状体脱位或移位，进而可导致视力暂时或永久丧失。本研究的目的是确定天冬氨酰/天冬酰胺酰羟化酶（ASPH，一种依赖2-酮戊二酸和铁的羟化酶）的预测底物，这可能解释了与ASPH相关综合征的晶状体不稳定表型。
对一名患有球形晶状体和高度近视的欧洲血统先证者进行外显子组测序。在瑞士蛋白质数据库中鉴定含有ASPH羟化基序的蛋白质。
我们在人类蛋白质组中鉴定出105种ASPH介导羟化的假定底物，其中两种（原纤维蛋白-1和潜伏转化生长因子β结合蛋白-2）与遗传性晶状体异位综合征相关，并且对微原纤维和睫状小带的发育至关重要。
我们的结果表明ASPH介导的羟化参与了FBN1/LTBP2微原纤维束和正常睫状小带的形成。
