Accumulation of sequence variants in genes of Wnt signaling and focal adhesion pathways in human corneas further explains their involvement in keratoconus

Karolak, Justyna A.; Gambin, Tomasz; Rydzanicz, Małgorzata; Polakowski, Piotr; Płoski, Rafał; Szaflik, Jacek P.; Gajęcka, Marzena

doi:10.7717/peerj.8982

Cited by 13 publications

(22 citation statements)

References 58 publications

(39 reference statements)

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“…Also, it indicates that abnormal expression of particular elements of the TGF-β, Hippo, and Wnt pathways might alter signaling crosstalk between these cascades in KTCN. Of note, our recent ES findings showed the accumulation of variants in several genes from Wnt signaling and/or focal adhesion pathways, deregulated in KTCN, further supporting possible involvement of these genes in disease etiology (Karolak et al, 2020).…”

Section: Discussionsupporting

confidence: 55%

“…The most significant downregulation was observed among genes belonging to the TGF-β, Hippo, and Wnt signaling and collagen synthesis and maturation networks that are responsible for proper corneal organization and regulation of corneal ECM remodeling (Kabza et al, 2017). Abnormalities within genes involved in ECM have also been reported in subsequent RNA-and DNA-based studies (Khaled et al, 2018;You et al, 2018;Sharif et al, 2019;Karolak et al, 2020). Thus, disruptions within these molecular cascades could be potentially responsible for corneal changes underlying the development of KTCN.…”

Section: Introductionmentioning

confidence: 97%

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Further evaluation of differential expression of keratoconus candidate genes in human corneas

Karolak

Ginter-Matuszewska

Tomela

et al. 2020

PeerJ

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Background Keratoconus (KTCN) is a progressive eye disease, characterized by changes in the shape and thickness of the cornea that results in loss of visual acuity. While numerous KTCN candidate genes have been identified, the genetic etiology of the disease remains undetermined. To further investigate and verify the contribution of particular genetic factors to KTCN, we assessed 45 candidate genes previously indicated as involved in KTCN etiology based on transcriptomic and genomic data. Methods The RealTime ready Custom Panel, covering 45 KTCN candidate genes and two reference transcripts, has been designed. Then, the expression profiles have been assessed using the RT-qPCR assay in six KTCN and six non-KTCN human corneas, obtained from individuals undergoing a penetrating keratoplasty procedure. Results In total, 35 genes exhibiting differential expression between KTCN and non-KTCN corneas have been identified. Among these genes were ones linked to the extracellular matrix formation, including collagen synthesis or the TGF-β, Hippo, and Wnt signaling pathways. The most downregulated transcripts in KTCN corneas were CTGF, TGFB3, ZNF469, COL5A2, SMAD7, and SPARC, while TGFBI and SLC4A11 were the most upregulated ones. Hierarchical clustering of expression profiles demonstrated almost clear separation between KTCN and non-KTCN corneas. The gene expression levels determined using RT-qPCR showed a strong correlation with previous RNA sequencing (RNA-Seq) results. Conclusions A strong correlation between RT-qPCR and earlier RNA-Seq data confirms the possible involvement of genes from collagen synthesis and the TGF-β, Hippo, and Wnt signaling pathways in KTCN etiology. Our data also revealed altered expression of several genes, such as LOX, SPARC, and ZNF469, in which single nucleotide variants have been frequently identified in KTCN. These findings further highlight the heterogeneous nature of KTCN.

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Section: Discussionsupporting

confidence: 55%

Section: Introductionmentioning

confidence: 97%

Further evaluation of differential expression of keratoconus candidate genes in human corneas

Karolak

Ginter-Matuszewska

Tomela

et al. 2020

PeerJ

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“… 45 P4HB encodes an enzyme involved in the hydroxylation of prolyl residues in preprocollagen, which serves to stabilize the collagen triple helices. 46 Our findings suggest that some nuclear genes, due to their involvement in ECM organization and collagen synthesis or focal adhesion pathways, which were previously indicated as being deregulated in Polish KTCN corneas based on DNA and RNA studies, 20 , 37 , 47 play a role in disease pathogenesis. However, the direct function of these genes and their impact on mitochondrial function or oxidative stress in KTCN remain to be elucidated.…”

Section: Discussionsupporting

confidence: 52%

Changes in Nuclear Gene Expression Related to Mitochondrial Function Affect Extracellular Matrix, Collagens, and Focal Adhesion in Keratoconus

Nowak-Malczewska

Karolak

Swierkowska

et al. 2021

Trans. Vis. Sci. Tech.

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Purpose Mitochondrial DNA (mtDNA) abnormalities were previously found to be causative in the pathogenesis of various diseases. Here, comprehensive mitochondrial and nuclear sequence and transcript analyses, along with analyses of the methylation aspects of nuclear genes related to mitochondrial function, were performed in patients with keratoconus (KTCN) to evaluate their contribution to the KTCN pathogenesis. Methods Blood mtDNA of 42 KTCN and 51 non-KTCN individuals was Sanger sequenced and analyzed along with the previously obtained corneal RNA-sequencing data of 20 KTCN and 21 non-KTCN individuals. In addition, the expression and methylation of mtDNA genes and 1223 mitochondria-related nuclear genes were evaluated. Results The mtDNA sequence alterations detected in blood coincided with variants identified in transcripts of the matched corneal tissues. In KTCN corneas, 97 mitochondria-related genes were deregulated, including TGFB1 , P4HB , and BCL2 , which are involved in the extracellular matrix (ECM) organization, collagen formation, and focal adhesion pathways. No changes in the expression of mtDNA transcripts and no differentially methylated genes among the assessed mitochondrial–nuclear gene sets were found. Conclusions The absence of corneal-specific mtDNA variants indicates that there is no direct relationship between mitochondrial sequence variability and KTCN phenotype in the studied individuals. However, the identified KTCN-specific transcriptomic alterations of the nuclear genes directly related to the mitochondria functioning point to their possible involvement in the ECM organization, collagen formation, and focal adhesion. Translational Relevance The identification of abnormalities within nuclear genes regulating ECM formation, collagen synthesis, and/or focal adhesion may form the basis of future treatment strategies or predict the progression of corneal changes in KTCN.

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“…More than half of the genes were reported in one type of study or in single studies. A few genes, encoded chains of collagens ( COL5A1, COL4A3 , and COL4A4 ) ( 57 , 59 , 61 , 67 , 72 , 76 , 78 , 84 , 87 , 88 , 90 ), collagen cross-linking enzyme ( LOX ) ( 18 , 30 , 90 ), factor for the synthesis or organization of collagen fibers ( ZNF469 ) ( 27 , 32 , 34 , 46 , 47 , 62 , 65 ), and others ( MIR184 and VSX1 ) ( 6 , 7 , 16 , 19 , 24 , 40 , 56 , 82 , 85 ) were identified in different types of studies, such as pathogenic mutation analysis, polymorphism association analysis, and family-based linkage analysis. However, the occurrence rate of these gene mutations in the population was relatively low, and in many populations, it could not even be verified ( 25 , 195 – 202 ), which suggested that KC is genetically heterogeneous.…”

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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Accumulation of sequence variants in genes of Wnt signaling and focal adhesion pathways in human corneas further explains their involvement in keratoconus

Cited by 13 publications

References 58 publications

Further evaluation of differential expression of keratoconus candidate genes in human corneas

Further evaluation of differential expression of keratoconus candidate genes in human corneas

Changes in Nuclear Gene Expression Related to Mitochondrial Function Affect Extracellular Matrix, Collagens, and Focal Adhesion in Keratoconus

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

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