Novel MIP gene mutation causes autosomal-dominant congenital cataract.

AIM: To identify disease-causative mutations in families with congenital cataract. METHODS: Two Chinese families with autosomal-dominant congenital cataract (ADCC) were recruited and underwent comprehensive eye examinations. Gene panel next-generation sequencing of common pathogenic genes of congenital cataract was performed in the proband of each family. Sanger sequencing was used to valid the candidate gene mutations and sequence the other family members for co-segregation analysis. The effect of sequence changes on protein structure and function was predicted through bioinformatics analysis. Major intrinsic protein (MIP)-wildtype and MIP-G29R plasmids were constructed and microinjected into zebrafish single-cell stage embryos. Zebrafish embryonic lens phenotypes were screened using confocal microscopy. RESULTS: A novel heterozygous mutation (c.85G>A; p.G29R) in the MIP gene was identified in the proband of one family. A known heterozygous mutation (c.97C>T; p.R33C; rs864309693) in MIP was found in the proband of another family. In-silico prediction indicated that the novel mutation might affect the MIP protein function. Zebrafish embryonic lens was uniformly transparent in both wild-type PCS2+MIP and mutant PCS2+MIP. CONCLUSION: Two missense mutations in the MIP gene in Chinese cataract families are identified, and one of which is novel. These findings expand the genetic spectrum of MIP mutations associated with cataracts. The functional studies suggest that the novel MIP mutation might not be a gain-of-function but a loss-of-function mutation.

First Evidence Indicates the Physiology- and Axial-Myopia-Dependent Profiles of Steroid Hormones in Aqueous Humor.

The quantitative level of steroid hormones (SHs) in some body fluids have been accepted for clinical diagnosis, whereas their distribution in aqueous humor (AH) is unknown yet. Herein, a profiling study was conducted with a total of 171 AH and 107 plasma samples using liquid chromatography coupled with tandem mass spectrometry (LC MS/MS). For the first time, six kinds of SHs in AH were quantitatively estimated, and their abundances were ranked at cortisol (F), corticosterone (COR), androstenedione (A2), and 11-deoxycortisol (11DOC). The corresponding abundance of all SHs in AH was significantly lower than those in plasma, while there was a lack of a proportional relationship with the abundance of plasma SHs. Dehydroepiandrosterone sulfate, the most abundant plasma SH, was undetectable in AH, implying that the blood-aqueous barrier might specifically block its transferral. Axial myopia generally results from many factors throughout the entire eye from tissues and molecules; furthermore, the correlation of AH SHs and axial myopia was assessed to look for their indication in such myopia. The panel with five kinds of AH SHs (F, COR, CORT, ALD and A2) was functional as a discriminator for axial myopia and control. The abundance of SHs, therefore, has a specific distribution in AH and can potentially contribute to axial myopia.

Development and Validation of a Novel Ferroptosis-Related LncRNA Signature for Predicting Prognosis and the Immune Landscape Features in Uveal Melanoma.

Background: Ferroptosis is a newly iron-dependent mode of programmed cell death that is involved in a variety of malignancies. But no research has shown a link between ferroptosis-related long non-coding RNAs (FRLs) and uveal melanoma (UM). We aimed to develop a predictive model for UM and explore its potential function in relation to immune cell infiltration. Methods: Identification of FRLs was performed using the Cancer Genome Atlas (TCGA) and FerrDb databases. To develop a prognostic FRLs signature, univariate Cox regression and least absolute shrinkage and selection operator (LASSO) were used in training cohort. Kaplan-Meier (K-M) and receiver operating characteristic (ROC) curve analyses were used to assess the reliability of the risk model. The immunological functions of FRLs signature were determined using gene set enrichment analysis (GSEA). Immunological cell infiltration and immune treatment were studied using the ESTIMATE, CIBERSORT, and ssGSEA algorithms. Finally, in vitro assays were carried out to confirm the biological roles of FRLs with known primer sequences (LINC00963, PPP1R14B.AS1, and ZNF667.AS1). Results: A five-genes novel FRLs signature was identified. The mean risk score generated by this signature was used to create two risk groups. The high-risk score UM patients had a lower overall survival rate. The area under the curve (AUC) of ROC and K-M analysis further validated the strong prediction capacity of the prognostic signature. Immune cells such as memory CD8 T cells, M1 macrophages, monocytes, and B cells showed a substantial difference between the two groups. GSEA enrichment results showed that the FRLs signature was linked to certain immune pathways. Moreover, UM patients with high-risk scores were highly susceptible to several chemotherapy drugs, such as cisplatin, imatinib, bortezomib, and pazopanib. Finally, the experimental validation confirmed that knockdown of three identified lncRNA (LINC00963, PPP1R14B.AS1, and ZNF667.AS1) suppressed the invasive ability of tumor cells in vitro. Conclusion: The five-FRLs (AC104129.1, AC136475.3, LINC00963, PPP1R14B.AS1, and ZNF667.AS1) signature has effects on clinical survival prediction and selection of immunotherapies for UM patients.