Dataset Information

Novel Mutations in COL6A3 That Associated With Peters' Anomaly Caused Abnormal Intracellular Protein Retention and Decreased Cellular Resistance to Oxidative Stress.

ABSTRACT: Peters' anomaly (PA) is a rare form of anterior segment dysgenesis characterized by central corneal opacity accompanied by iridocorneal or lenticulo-corneal adhesions. Although genetic mutations, particularly those affecting transcription factors that function in eye development, are known to cause PA, the etiology of this disease remains poorly understood. In this study, 23 patients with PA were recruited for panel sequencing. Four out of 23 patients were found to carry variants in known PA causal genes, PITX2 and PITX3. More importantly, two homozygous mutations (NM_057164: p.Val86Ala and p.Arg689Cys) in the COL6A3 gene (collagen type VI alpha-3 chain) that correlated with the phenotype of type I PA were identified, and then validated by following whole-exome sequencing. The expression profile of the COL6A3 gene in the cornea and the impact of the mutations on protein physiological processing and cellular function were further explored. It was shown that COL6A3 presented relatively high expression in the cornea. The mutant COL6A3 protein was relatively retained intracellularly, and its expression reduced cellular resistance to oxidative stress through an enhanced endoplasmic reticulum stress response. Taken together, our findings expanded the known genetic spectrum of PA, and provided evidence for the involvement of COL6A3 or collagen VI in ocular anterior segment development, thereby offering new insight for future investigations targeting PA.

SUBMITTER: Li Y

PROVIDER: S-EPMC7693641 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Novel Mutations in <i>COL6A3</i> That Associated With Peters' Anomaly Caused Abnormal Intracellular Protein Retention and Decreased Cellular Resistance to Oxidative Stress.

Li Yue Y Zhang Jing J Dai Yiqin Y Fan Yidan Y Xu Jianjiang J

Frontiers in cell and developmental biology 20201110

Peters' anomaly (PA) is a rare form of anterior segment dysgenesis characterized by central corneal opacity accompanied by iridocorneal or lenticulo-corneal adhesions. Although genetic mutations, particularly those affecting transcription factors that function in eye development, are known to cause PA, the etiology of this disease remains poorly understood. In this study, 23 patients with PA were recruited for panel sequencing. Four out of 23 patients were found to carry variants in known PA cau ...[more]

PMID: 33304895

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Project description:FOXE3 is a lens specific transcription factor that has been associated with anterior segment ocular dysgenesis. To determine the transcriptional target(s) of FOXE3 that are indispensable for the anterior segment development, we examined the transcriptome and the proteome of cells expressing truncated FOXE3 responsible for Peters anomaly identified through linkage-coupled next-generation whole exome sequencing. We found that DNAJB1, an autophagy-associated protein, was the only candidate exhibiting differential expression in both screens. We confirmed the candidacy of DNAJB1 through chromatin immunoprecipitation and luciferase assays while knockdown of DNAJB1 in human lens epithelial cells resulted in mitotic arrest. Subsequently, we targeted dnajb1a in zebrafish through injection of a splice-blocking morpholino. The dnajb1a morphants exhibited underdeveloped cataractous lenses with persistent apoptotic nuclei. In conclusion, we have identified DNAJB1 as a transcriptional target of FOXE3 in a novel pathway that is crucial for development of the anterior segment of the eye. Human Embryonic Kidney (HEK293FT) cells were transfected with the expression vector (pT-RexTM-DEST30) harboring either the wild type or the mutant (C240*) FOXE3 ORF (open reading frame). The experimental design included a total of eight biological replicates of cells expressing the wild type and eight replicates of mutant FOXE3 along with eight non-transfected controls. Cells were harvested 24-hour post-transfection and subjected to total RNA isolation for the preparation of whole transcriptome next-generation sequencing libraries. Initially, we examined the quality of transcriptome libraries on a MiSeq genome analyzer. Subsequent to confirmation of the quality, all libraries were paired-end sequenced (2 x 100 bp) using Illumina TruSeq Cluster V3 flow cell at a concentration of 13.0 pM in two separate lanes (12 bar-coded mRNA pooled libraries in each lane) on a HiSeq 2000 genome analyzer.

Dataset Information

Novel Mutations in COL6A3 That Associated With Peters' Anomaly Caused Abnormal Intracellular Protein Retention and Decreased Cellular Resistance to Oxidative Stress.

Publications

Novel Mutations in <i>COL6A3</i> That Associated With Peters' Anomaly Caused Abnormal Intracellular Protein Retention and Decreased Cellular Resistance to Oxidative Stress.

Similar Datasets

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