Evaluation of TGFBI corneal dystrophy and molecular diagnostic testing

Chao-Shern, Connie; DeDionisio, Larry; Jang, Jun-Heok; Chan, Clara C.; Thompson, Vance; Christie, Kathleen A.; Nesbit, M. Andrew; McMullen, C.B. Tara

doi:10.1038/s41433-019-0346-x

Cited by 24 publications

(20 citation statements)

References 24 publications

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“…The present study demonstrated that the mutations in the codons of R124 and R555, such as, R124H, R555W and R124C were the most common mutations in a multi-ethnic population in Singapore, corroborating well with the results of previous studies in different countries [ 2 , 5 , 8 , 19 , 20 , 21 , 22 , 23 , 24 ]. The predominance of R124H, R555W and R124C mutations in various geographical locations worldwide indicates that these mutations may represent mutation hot spots in the gene [ 2 ].…”

Section: Discussionsupporting

confidence: 92%

Genotypic Homogeneity in Distinctive Transforming Growth Factor-Beta Induced (TGFBI) Protein Phenotypes

Han

Venkatraman

Wong

et al. 2021

IJMS

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Background: To evaluate the distribution of the transforming growth factor-beta induced (TGFBI) corneal dystrophies in a multi-ethnic population in Singapore, and to present the different phenotypes with the same genotype. Methods: This study included 32 patients. Slit lamp biomicroscopy was performed for each patient to determine the disease phenotype. Genomic DNA was extracted from the blood samples and the 17 exons of the TGFBI gene were amplified by PCR and sequenced bi-directionally for genotype analysis. Results: Regarding phenotypes, the study patients comprised 11 (34.4%; 8 with R555W and 3 with R124H mutation) patients with granular corneal dystrophy type 1 (GCD1), 6 (18.8%; 5 with R124H and 1 with R124C mutation) patients with GCD2, 13 (40.6%; 7 with R124C, 2 with H626R, 2 with L550P, 1 with A620D and 1 with H572R) patients with lattice corneal dystrophy (LCD) and 2 (6.3%; 1 with R124L and 1 with R124C) patients with Reis–Bückler corneal dystrophy. Regarding genotype, R124H mutation was associated with GCD2 (5 cases; 62.5%) and GCD1 (3 cases; 37.5%). R124C mutation was associated with LCD (7 cases; 87.5%) and GCD2 (1 case; 12.5%). All the 8 cases (100%) of R555W mutation were associated with GCD1. Conclusions: Although the association between genotype and phenotype was good in most cases (65.7%; 21 of 32 patients), genotype/phenotype discrepancy was observed in a significant number.

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Section: Discussionsupporting

confidence: 92%

Genotypic Homogeneity in Distinctive Transforming Growth Factor-Beta Induced (TGFBI) Protein Phenotypes

Han

Venkatraman

Wong

et al. 2021

IJMS

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“…Our results provide a novel mechanistic insight into the function of DNA methylation in the pathogenesis of FECD and support further studies to determine how methylation of miR-199b-5p may be used as a clinical biomarker of phenotype expression in FECD. In the past few years, there have been major advances in testing blood, saliva, and cheek swab samples to genetically screen for corneal dystrophies 87,88 . Further studies are needed to determine if DNA methylation changes can be detected in these tissue samples that correspond to corneal methylation changes.…”

Section: Discussionmentioning

confidence: 99%

Aberrant DNA methylation of miRNAs in Fuchs endothelial corneal dystrophy

Pan

Weisenberger

Zheng

et al. 2019

Sci Rep

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Homeostatic maintenance of corneal endothelial cells is essential for maintenance of corneal deturgescence and transparency. in fuchs endothelial corneal dystrophy (fecD), an accelerated loss and dysfunction of endothelial cells leads to progressively severe visual impairment. An abnormal accumulation of extracellular matrix (ecM) is a distinctive hallmark of the disease, however the molecular pathogenic mechanisms underlying this phenomenon are not fully understood. Here, we investigate genome-wide and sequence-specific DNA methylation changes of miRNA genes in corneal endothelial samples from fecD patients. We discover that miRnA gene promoters are frequent targets of aberrant DNA methylation in FECD. More specifically, miR-199B is extensively hypermethylated and its mature transcript miR-199b-5p was previously found to be almost completely silenced in FECD. Furthermore, we find that miR-199b-5p directly and negatively regulates Snai1 and ZEB1, two zinc finger transcription factors that lead to increased ECM deposition in FECD. Taken together, these findings suggest a novel epigenetic regulatory mechanism of matrix protein production by corneal endothelial cells in which miR-199B hypermethylation leads to miR-199b-5p downregulation and thereby the increased expression of its target genes, including Snai1 and ZEB1. our results support miR-199b-5p as a potential therapeutic target to prevent or slow down the progression of FECD disease. Corneal transparency is critical for good visual acuity. The corneal endothelium regulates the hydration status of the cornea and has an essential role in maintaining corneal deturgescence and preventing edema that can degrade corneal transparency. It is the innermost layer of the cornea and is composed of a single layer of cells that pump excess fluid out of the cornea through active ion-transport processes 1,2. Fuchs endothelial corneal dystrophy (FECD) is a bilateral, slowly progressive disorder in which the corneal endothelial cells are diseased and become less efficient at removing fluid. As a result, the highly ordered arrangement of collagen fibers in the corneal stromal layer become disrupted, leading to corneal opacification and vision loss 3. Other clinical phenotypic changes that occur in FECD include an excessive accumulation of extracellular matrix (ECM), formation of central excrescences (corneal guttae), thickening of Descemet's membrane, and corneal scarring 4. At earlier stages of FECD, the formation of corneal guttae can cause light scatter and optical aberrations that can impair vision, even in the absence of overt corneal edema. In later FECD, overt endothelial dysfunction and resultant corneal edema contribute significantly to visual loss. Corneal endothelial cells are largely non-regenerative in vivo and their loss is often irreversible 5. Medical management is often inadequate and corneal endothelial transplantation remains the main therapeutic option to restore vision in patients with advanced FECD. FECD is a leading indication for corneal transplantation i...

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“…The TGFBI is a significant component of human corneal stroma involved in cell adhesion and migration, which is induced by its interaction with several ECM elements, including collagens ( Runager, Enghild & Klintworth, 2008 ). TGFBI variants have been frequently identified in patients with corneal dystrophies ( Chao-Shern et al, 2019 ), as well as KTCN ( Guan et al, 2012 ). While a significant upregulation of TGFBI in KTCN patients compared to control individuals was also detected previously ( Bykhovskaya et al, 2016a ), in most transcriptomic or proteomic studies the level of TGFBI in KTCN tissues was decreased ( Takács et al, 1999 ; Zhao et al, 2002 ).…”

Section: Discussionmentioning

confidence: 99%

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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Evaluation of TGFBI corneal dystrophy and molecular diagnostic testing

Cited by 24 publications

References 24 publications

Genotypic Homogeneity in Distinctive Transforming Growth Factor-Beta Induced (TGFBI) Protein Phenotypes

Genotypic Homogeneity in Distinctive Transforming Growth Factor-Beta Induced (TGFBI) Protein Phenotypes

Aberrant DNA methylation of miRNAs in Fuchs endothelial corneal dystrophy

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

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