Role of extracellular matrix remodelling gene SNPs in keratoconus

Abdullah, Omnia; Gazzar, Walaa Bayoumie El; Salem, Tamer; Al-Kamil, Eman

doi:10.1080/09674845.2019.1654346

Cited by 8 publications

(3 citation statements)

References 31 publications

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“…Among them, just five genes (WNT16, CD248, COL6A2, COL4A3, and ADAMTS3) were predicted as "disease causing" and expressed in normal HCF cells. Among them, COL4A3 is a reported candidate genes of KC [37,38]. However, its variant was not cosegregation with the phenotype of the family, indicating that this variant cannot fully explain the cause of the disease.…”

Section: Discussionmentioning

confidence: 99%

Multi-level consistent changes of the ECM pathway identified in a typical keratoconus twin’s family by multi-omics analysis

Hao

Chen

Zhang

et al. 2020

Orphanet J Rare Dis

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Background: Keratoconus (KC) is a common, degenerative disorder of the cornea, and genetic factors play a key role in its development. However, the genetic etiology of KC is still unclear. This study used the family of twins as material, using, for the first time, multi-omics analysis, to systematically display the changes in KC candidate factors in patients at the DNA, RNA, and protein levels. These can evaluate candidate pathogenic factors in depth and lock onto pathogenic targets. Results: The twins in this study presented classic phenotypes, clear diagnoses, complete case data, and clinical samples, which are excellent materials for genetically studying KC. Whole-exome sequencing was conducted on both the twins and their parents. Transcriptome sequencing was conducted on proband's and health individual's primary human corneal fibroblast cells. Quantitative Real-time PCR and western blot were used to validate the differential gene expressions between the proband and controls. By integrating genomics, transcriptome, and protein level data, multiple consecutive events of KC were systematically analyzed to help better understand the molecular mechanism and genetic basis of KC. The results showed that the accumulation of rare, micro-effect risk variants was the pathogenic factor in this Chinese KC family. Consistent changes in extracellular matrices (ECMs) at the DNA and RNA levels suggested that ECM related changes play a key role in KC pathogenesis. The major gene variants (WNT16, CD248, COL6A2, COL4A3 and ADAMTS3) may affect the expression of related collagens or ECM proteins, thus reducing the amount of ECM in corneas and resulting in KC. Conclusions: This study, the first to explore the genetic etiology of KC via multi-omics analysis under the polygenetic model, has provided new insights into the genetic mechanisms underlying KC and an effective strategy for studying KC pathogenesis in the future.

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Section: Discussionmentioning

confidence: 99%

Multi-level consistent changes of the ECM pathway identified in a typical keratoconus twin’s family by multi-omics analysis

Hao

Chen

Zhang

et al. 2020

Orphanet J Rare Dis

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“…The environmental factors may include endogenous and exogenous factors, such as glucocorticoid, hydrogen peroxide, and reactive oxygen species (ROS) ( 120 ). The gene mutations or variants involved in collagen ( 57 , 61 , 64 , 67 , 75 , 76 , 78 , 88 ), metallopeptidase inhibitor ( 75 , 81 , 109 , 157 ), lysyl oxidase ( 18 , 30 , 81 , 90 ), metallopeptidase ( 64 ), antioxidant enzyme ( 16 , 25 , 81 , 199 ), inflammatory cytokines ( 11 , 45 , 83 , 201 ), and others cause insufficient protein dosage or abnormal function. These genetic changes, together with the aforementioned stimulation, lead to the changes in related functions and pathways in the corneal cells.…”

Section: Discussionmentioning

confidence: 99%

Systematically Displaying the Pathogenesis of Keratoconus via Multi-Level Related Gene Enrichment-Based Review

Hao

Gao

et al. 2022

Front. Med.

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Keratoconus (KC) is an etiologically heterogeneous corneal ectatic disorder. To systematically display the pathogenesis of keratoconus (KC), this study reviewed all the reported genes involved in KC, and performed an enrichment analysis of genes identified at the genome, transcription, and protein levels respectively. Combined analysis of multi-level results revealed their shared genes, gene ontology (GO), and pathway terms, to explore the possible pathogenesis of KC. After an initial search, 80 candidate genes, 2,933 transcriptional differential genes, and 947 differential proteins were collected. The candidate genes were significantly enriched in extracellular matrix (ECM) related terms, Wnt signaling pathway and cytokine activities. The enriched GO/pathway terms of transcription and protein levels highlight the importance of ECM, cell adhesion, and inflammatory once again. Combined analysis of multi-levels identified 13 genes, 43 GOs, and 12 pathways. The pathogenic relationships among these overlapping factors maybe as follows. The gene mutations/variants caused insufficient protein dosage or abnormal function, together with environmental stimulation, leading to the related functions and pathways changes in the corneal cells. These included response to the glucocorticoid and reactive oxygen species; regulation of various signaling (P13K-AKT, MAPK and NF-kappaB), apoptosis and aging; upregulation of cytokines and collagen-related enzymes; and downregulation of collagen and other ECM-related proteins. These undoubtedly lead to a reduction of extracellular components and induction of cell apoptosis, resulting in the loosening and thinning of corneal tissue structure. This study, in addition to providing information about the genes involved, also provides an integrated insight into the gene-based etiology and pathogenesis of KC.

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“…The matrix metalloproteinases (MMPs) are a group of extracellular endopeptidases with a key role in extracellular matrix remodelling by degrading various types of collagen [4]. The study [5] examined the effect of SNPs in the genes for collagen type 4 (COL4A3), TIMP-1 (a gene for one of the tissue inhibitors of MMPs) and MMP-9. As the TIMP-1 gene is on the X chromosome, male and female subjects were investigated separately.…”

Section: Molecular Genetic Studiesmentioning

confidence: 99%

British Journal of Biomedical Science in 2020. What have we learned?

Brown

Orchard

Rhodes

2020

British Journal of Biomedical Science

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Each year the British Journal of Biomedical Science publishes a 'What have we learned' editorial designed to introduce readers within the major disciplines of laboratory medicine to developments outside their immediate area. In addition it is designed to inform a wider readership of the advances in the diagnosis and treatment of disease. To this end, in 2020 the journal published 39 articles covering the disciplines within Biomedical Science in the 4 issues comprising volume 77. These included a review of COVID-19 in this issue, 27 original articles, 6 Biomedical Science 'In Brief' and 4 case histories. 27 of the articles involved molecular techniques, with one of these comparing results with a mass spectrometry based method. The preponderance of molecular genetic studies gives us a good idea of the likely future direction of the disciplines

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Role of extracellular matrix remodelling gene SNPs in keratoconus

Cited by 8 publications

References 31 publications

Multi-level consistent changes of the ECM pathway identified in a typical keratoconus twin’s family by multi-omics analysis

Multi-level consistent changes of the ECM pathway identified in a typical keratoconus twin’s family by multi-omics analysis

Systematically Displaying the Pathogenesis of Keratoconus via Multi-Level Related Gene Enrichment-Based Review

British Journal of Biomedical Science in 2020. What have we learned?

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