Mutation update:<i>TGFBI</i>pathogenic and likely pathogenic variants in corneal dystrophies

Kheir, Valeria; Cortés‐González, Vianney; Ruíz, Juan-Carlos; Schorderet, Daniel F.

doi:10.1002/humu.23737

Cited by 32 publications

(18 citation statements)

References 138 publications

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“…Only few Cases have been reported in European population, the United States, Japanese's and other ethnicities, but none in North African population (18,19). To our knowledge, in the TGFBI gene and in the same position, the mutations (p.Arg555Gln; p.Arg555Trp), have been also reported by Xiang et al and Yu y et al (20,21) and were correlated with TBCD (7,22,23). In this study, we identi ed a novel mutation in TGFBI gene (c.1772C>A; p.Ser591Tyr).…”

Section: Discussionsupporting

confidence: 52%

“…To our knowledge, 69 disease-associated variants in the transforming growth factor beta-induced gene (TGFBI, OMIM 601692) have been described as involved in different subtypes of CDs in patients. The IC3D classi cation describes TGFBI-linked dystrophies by the recognition that they affect multiple layers rather than being con ned to one corneal layer (7)(8)(9)(10)(11)(12)(13)(14). Several phenotypes have been described according to the corneal layer alteration and the Investigation of pathogenic mutations in the TGFBI gene, with the exception of metabolic affections.…”

Section: Introductionmentioning

confidence: 99%

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Novel mutation in the TGFBI gene in a Moroccan family with atypical corneal dystrophy: a case report.

BENBOUCHTA

Jaouad

TAZI³

et al. 2020

Preprint

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Background: Corneal dystrophies (CDs) are a heterogeneous group of bilateral, genetically determined, non-inflammatory bilateral corneal diseases which are usually limited to the cornea. CD is characterized by a large variability in the age of onset, evolution and visual impact and the accumulation of insoluble deposits at different depths of the cornea. Clinical symptoms revealed bilaterally multiple superficial, epithelial, and stromal anterior granular opacities, in different stages of severity among three patients of this family. 99 genes are involved in CDs.The aim of this study is to identify pathogenic variant caused atypical corneal dystrophy in a large Moroccan family and to describe the clinical phenotype with their severe different stages of evolution.Case presentation: In this study, we report a large Moroccan family with CD. Whole Exome Sequencing (WES) was performed in the three affected members who shared a phenotype of a corneal dystrophy in different stages of severity. The variant validation and familial segregation were done by Sanger sequencing in affected sister and mothers and in two unaffected brothers. Whole exome sequencing showed a novel heterozygous mutation (c.1772C>A; p.Ser591Tyr) in TGFBI gene. Clinical examinations demonstrated bilaterally multiple superficial, epithelial and stromal anterior granular opacities; in different stages of severity among three patients of this family. Conclusions: This report presents a novel mutation in TGFBI gene, found in three family members affected with different phenotypic aspects. This mutation is associated with Thiel-Behnke corneal dystrophy and therefore, it could be considered as a novel phenotype genotype correlation, which will help in genetic counseling for this family

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Section: Discussionsupporting

confidence: 52%

Section: Introductionmentioning

confidence: 99%

Novel mutation in the TGFBI gene in a Moroccan family with atypical corneal dystrophy: a case report.

BENBOUCHTA

Jaouad

TAZI³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Only a few cases have been reported in European populations, the United States, Japanese populations and other ethnicities, but none have been reported in North African populations (18,19). To our knowledge, mutations (p.Arg555Gln; p.Arg555Trp) in the TGFBI gene and in the same position have also been reported by Xiang et al and Yu Y et al (20,21) and were correlated with TBCD (7,22,23). In this study, we identi ed a novel mutation in the TGFBI gene (c.1772C>A; p.Ser591Tyr).…”

Section: Discussionmentioning

confidence: 60%

“…To our knowledge, 69 disease-associated variants in the transforming growth factor beta-induced gene (TGFBI, OMIM 601692) have been described as being involved in different CD subtypes in patients. The IC3D classi cation describes TGFBI-linked dystrophies by the recognizing that they affect multiple layers rather than being con ned to one corneal layer (7)(8)(9)(10)(11)(12)(13)(14). Several phenotypes have been described according to corneal layer alterations and the investigation of pathogenic mutations in the TGFBI gene, with the exception of metabolic effects.…”

Section: Introductionmentioning

confidence: 99%

Novel mutation in the TGFBI gene in a Moroccan family with atypical corneal dystrophy: a case report

BENBOUCHTA

Jaouad

TAZI³

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Corneal dystrophies (CDs) are a heterogeneous group of bilateral, genetically determined, noninflammatory bilateral corneal diseases that are usually limited to the cornea. CD is characterized by a large variability in the age of onset, evolution and visual impact and the accumulation of insoluble deposits at different depths in the cornea. Clinical symptoms revealed bilateral multiple superficial, epithelial, and stromal anterior granular opacities in different stages of severity among three patients of this family. A total of 99 genes are involved in CDs. The aim of this study was to identify pathogenic variants causing atypical corneal dystrophy in a large Moroccan family and to describe the clinical phenotype with severely different stages of evolution. Case presentation: In this study, we report a large Moroccan family with CD. Whole-exome sequencing (WES) was performed in the three affected members who shared a phenotype of corneal dystrophy in different stages of severity. Variant validation and familial segregation were performed by Sanger sequencing in affected sisters and mothers and in two unaffected brothers. Whole-exome sequencing showed a novel heterozygous mutation (c.1772C>A; p.Ser591Tyr) in the TGFBI gene. Clinical examinations demonstrated bilaterally multiple superficial, epithelial and stromal anterior granular opacities in different stages of severity among three patients in this family. Conclusions: This report describes a novel mutation in the TGFBI gene found in three family members affected by different phenotypic aspects. This mutation is associated with Thiel-Behnke corneal dystrophy; therefore, it could be considered a novel phenotype genotype correlation, which will help in genetic counselling for this family.

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“…TGFBIp consists of a secretory signal peptide, a domain rich in cysteine residues, a cell attachment tripeptide Arg-Gly-Asp (RGD) signal residue, and four Fasciclin 1 (FAS-1) domains 9,10 . The TGFBI gene has 74 mutations reported to date 11 , and the mutant protein is associated with modified protein stability, altered proteolytic processing, and deposition of insoluble aggregates in various layers of the cornea [12][13][14][15][16] . The aggregation and deposition of TGFBIp display different clinical phenotypes; the deposits range from amyloidogenic structures to amorphous granular deposits, or a combination of both 17 .…”

mentioning

confidence: 99%

Effect of osmolytes on in-vitro aggregation properties of peptides derived from TGFBIp

Venkatraman

Murugan

Lin

et al. 2020

Sci Rep

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Protein aggregation has been one of the leading triggers of various disease conditions, such asAlzheimer's, Parkinson's and other amyloidosis. TGFBI-associated corneal dystrophies are protein aggregation disorders in which the mutant TGFBIp aggregates and accumulates in the cornea, leading to a reduction in visual acuity and blindness in severe cases. Currently, the only therapy available is invasive and there is a known recurrence after surgery. In this study, we tested the inhibitory and amyloid dissociation properties of four osmolytes in an in-vitro TGFBI peptide aggregation model. The 23-amino acid long peptide (TGFBIp 611-633 with the mutation c.623 G>R) from the 4th FAS-1 domain of TGFBIp that rapidly forms amyloid fibrils was used in the study. Several biophysical methods like Thioflavin T (ThT) fluorescence, Circular Dichroism (CD), fluorescence microscopy and Transmission electron microscopy (TEM) were used to study the inhibitory and amyloid disaggregation properties of the four osmolytes (Betaine, Raffinose, Sarcosine, and Taurine). The osmolytes were effective in both inhibiting and disaggregating the amyloid fibrils derived from TGFBIp 611-633 c.623 G>R peptide. The osmolytes did not have an adverse toxic effect on cultured human corneal fibroblast cells and could potentially be a useful therapeutic strategy for patients with TGFBIp corneal dystrophies. Cytotoxicity of osmolytes on cultured human corneal fibroblast (HCF). Real-time live-cell imagingby IncuCyte. For real-time observation of the effect of the osmolytes on cultured human corneal fibroblast, 3000 cells/well were seeded in 96-well plates and placed in an incubator at 37 °C for 24 h to proliferate. Cells were then incubated with varying concentrations of the osmolytes (0.1 mM, 1 mM, 10 mM, 100 mM and 1000 mM) in triplicates and images were captured with IncuCyte ZOOM System (Essen BioScience Inc., Research Instruments, Singapore). Frames were then captured at 4-h intervals from 4 separate regions/well using a 10× objective for 20 h to observe cell toxicity. Scientific RepoRtS |(2020) 10:4011 | https://doi.

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Mutation update:TGFBIpathogenic and likely pathogenic variants in corneal dystrophies

Cited by 32 publications

References 138 publications

Novel mutation in the TGFBI gene in a Moroccan family with atypical corneal dystrophy: a case report.

Novel mutation in the TGFBI gene in a Moroccan family with atypical corneal dystrophy: a case report.

Novel mutation in the TGFBI gene in a Moroccan family with atypical corneal dystrophy: a case report

Effect of osmolytes on in-vitro aggregation properties of peptides derived from TGFBIp

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