Citation: Guo C, Zhao Z, Chen D, et al. Detection of clinically relevant genetic variants in Chinese patients with nanophthalmos by trio-based wholegenome sequencing study. Invest Ophthalmol Vis Sci. 2019;60:2904-2913. https://doi.org/10.1167 PURPOSE. Nanophthalmos is a rare genetic disorder commonly characterized by a short axial length (AL) and severe hyperopia. Mutations that have been identified through Mendelian genetic analysis can only explain a fraction of nanophthalmic cases. We investigate the clinically relevant genetic variants in nanophthalmos by whole-genome sequencing (WGS), including de novo mutations (DNMs) and inherited mutations. METHODS.Clinically relevant genetic variants of 11 trios (11 nanophthalmic probands and their unaffected parents) from the Zhongshan Ophthalmic Center, China, were analyzed by WGS. We further screened three trios and 10 sporadic cases to identify the MYRF mutations.RESULTS. In two of 11 trios, without evidence of the presence of deleterious inherited autosomal variants, two DNMs of MYRF (c.789delC, p.S264fs and c.789dupC, p.S264fs) were identified in the probands. These loss-of-function DNMs were predicted to result in premature stop codons and protein structure damage in both probands. In addition, deleterious inherited genetic variants in PRSS56 and MFRP were found in eight probands of the other nine trios. Expanded screening found an additional MYRF DNM (c.1433G>C, p.R478P) in one trio and a stop-gain MYRF mutation (c.2956C>T, p.R986X) in one sporadic case, suggesting the recurrence of MYRF mutations in nanophthalmic patients.CONCLUSIONS. This is the first trio-based WGS study for nanophthalmos, revealing the potential role of DNMs in MYRF and rare inherited genetic variants in PRSS56 and MFRP. The underlying mechanism of MYRF in the development of nanophthalmos needs to be further investigated.

Here, we developed a novel deep network architecture called the multi-layered Long-Short Term Memory networks (LSTMs) approach for the prediction of protein interface residue pairs. Firstly, we created three new descriptions and used other six worked characterizations to describe an amino acid, then we employed these features to discriminate between interface residue pairs and non-interface residue pairs. Secondly, we used two thresholds to select residue pairs that are more likely to be interface residue pairs. Furthermore, this step increases the proportion of interface residue pairs and reduces the influence of imbalanced data. Thirdly, we built deep network architectures based on Long-Short Term Memory networks algorithm to organize and refine the prediction of interface residue pairs by employing features mentioned above. We trained the deep networks on dimers in the unbound state in the international Protein-protein Docking Benchmark version 3.0. The updated data sets in the versions 4.0 and 5.0 were used as the validation set and test set respectively. For our best model, the accuracy rate was over 62% when we chose the top 0.2% pairs of every dimer in the test set as predictions, which will be very helpful for the understanding of protein-protein interaction mechanisms and for guidance in biological experiments.

Our previous study demonstrated that gypenosides (Gp) exert protective effects on retinal nerve fibers and axons in a mouse model of experimental autoimmune optic neuritis. However, the therapeutic mechanisms remain unclear. Thus, in this study, a model of oxidative damage in retinal ganglion cells (RGCs) was established to investigate the protective effect of Gp, and its possible influence on oxidative stress in RGCs. Treatment of cells with H 2 O 2 induced RGC injury owing to the generation of intracellular reactive oxygen species (ROS). In addition, the activities of antioxidative enzymes decreased and the expression of inflammatory factors increased, resulting in an increase in cellular apoptosis. Gp helped RGCs to become resistant to oxidation damage by directly reducing the amount of ROS in cells and exerting protective effects against H 2 O 2-induced apoptosis. Treatment with Gp also reduced the generation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and increased nuclear respiratory factor 2 (Nrf-2) levels so as to increase the levels of heme oxygenase-1 (HO-1) and glutathione peroxidase 1/2 (Gpx1/2), which can enhance antioxidation in RGCs. In conclusion, our data indicate that neuroprotection by Gp involves its antioxidation and anti-inflammation effects. Gp prevents apoptosis through a mitochondrial apoptotic pathway. This finding might provide novel insights into understanding the mechanism of the neuroprotective effects of gypenosides in the treatment of optic neuritis.

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