Late-Onset Lattice Corneal Dystrophy Without Typical Lattice Lines Caused by a Novel Mutation in the TGFBI Gene

Ołdak, Monika; Szaflik, Jacek P.; Ścieżyńska, Aneta; Udziela, Monika; Maksym, Radosław; Rymgayłło-Jankowska, Beata; Hofmann-Rummelt, Carmen; Menzel‐Severing, Johannes; Płoski, Rafał; Żarnowski, Tomasz; Kruse, Friedrich E.; Szaflik, Jerzy

doi:10.1097/ico.0000000000000062

Cited by 13 publications

(6 citation statements)

References 25 publications

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“…TGFβIp-associated corneal dystrophies are phenotypically heterogeneous, inherited in an autosomal dominant manner 1 9 10 and are classified as lattice, granular, combined lattice and granular, Reis-Buckler and Thiel-Behnke corneal dystrophies 1 2 11 12 . So far, 64 single amino acid mutations associated with distinct phenotypes have been reported 4 13 14 . Among the four FAS1 domains of TGFβIp, the 1 st and 4th FAS1 domains carry the disease related mutations, with ~80% of the mutations residing in the 4 th _FAS1 domain 11 .…”

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confidence: 99%

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pH Induced Conformational Transitions in the Transforming Growth Factor β-Induced Protein (TGFβIp) Associated Corneal Dystrophy Mutants

Murugan

Venkatraman

Zhou

et al. 2016

Sci Rep

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Most stromal corneal dystrophies are associated with aggregation and deposition of the mutated transforming growth factor-β induced protein (TGFβIp). The 4th_FAS1 domain of TGFβIp harbors ~80% of the mutations that forms amyloidogenic and non-amyloidogenic aggregates. To understand the mechanism of aggregation and the differences between the amyloidogenic and non-amyloidogenic phenotypes, we expressed the 4th_FAS1 domains of TGFβIp carrying the mutations R555W (non-amyloidogenic) and H572R (amyloidogenic) along with the wild-type (WT). R555W was more susceptible to acidic pH compared to H572R and displayed varying chemical stabilities with decreasing pH. Thermal denaturation studies at acidic pH showed that while WT did not undergo any conformational transition, the mutants exhibited a clear pH-dependent irreversible conversion from αβ conformation to β-sheet oligomers. The β-oligomers of both mutants were stable at physiological temperature and pH. Electron microscopy and dynamic light scattering studies showed that β-oligomers of H572R were larger compared to R555W. The β-oligomers of both mutants were cytotoxic to primary human corneal stromal fibroblast (pHCSF) cells. The β-oligomers of both mutants exhibit variations in their morphologies, sizes, thermal and chemical stabilities, aggregation patterns and cytotoxicities.

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“…In lattice corneal dystrophies (LCD), the protein aggregates appear as lattice lines or amyloid fibrils (amyloidogenic). In granular corneal dystrophies (GCD), they appear as granular, non-amyloidogenic deposits 11 12 13 14 15 16 . Both phenotypes display significant differences in morphology, aggregation and tinctorial properties.…”

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confidence: 99%

pH Induced Conformational Transitions in the Transforming Growth Factor β-Induced Protein (TGFβIp) Associated Corneal Dystrophy Mutants

Murugan

Venkatraman

Zhou

et al. 2016

Sci Rep

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“…Immunohistochemical corneal analysis from a p.(L558P) carrier revealed the amyloidal nature of the deposits, supporting its classification as LCD. Several studies have also reported atypical LCD phenotypes associated with different TGFBI variants, which are characterized by a delayed onset of the clinical signs and symptoms (p.[P501T], p.[L527R], p.[L565P], p.[H626R] and p.[N622H]) and/or deep location of the amyloid deposits in the corneal stroma gene (p.[R496W], p.[L527R], p.[A546D], p.[G594 V] and p. [V631D]).…”

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confidence: 99%

Transforming growth factor beta‐induced p.(L558P) variant is associated with autosomal dominant lattice corneal dystrophy type IV in a large cohort of Spanish patients

Campos-Mollo

Varela-Conde

Arriola‐Villalobos

et al. 2019

Clinical Exper Ophthalmology

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Importance Rare transforming growth factor beta‐induced (TGFBI) gene variants are involved in autosomal dominant corneal dystrophies (CDs) with heterogeneous clinical features. Background The purpose of this study was to analyse TGFBI gene variants and genotype‐phenotype correlations in a cohort affected by atypical stromal CD. Design Retrospective cohort study (from May 2014 to September 2017). Participants Thirty‐five individuals from 10 unrelated South European families presenting atypical lattice CD (LCD) were included. Methods Corneal phenotypes were assessed by slit‐lamp examination and optical coherence tomography (OCT). Contrast sensitivity was measured under mesopic conditions. Genomic DNA was obtained from blood samples, and all 17 TGFBI exons were screened for variants by Sanger sequencing. Main Outcome Measures p.(L558P) variant of TGFBI gene. Results The p.(L558P) variant was identified in 22 members of the 10 families diagnosed with atypical LCD, characterized by late‐onset and absence of recurrent erosion syndrome. OCT revealed punctiform deposits in the deep‐mid stroma and normal anterior stroma. This variant was demonstrated to be transmitted with the disease according to autosomal dominant inheritance in most families. Conclusions and Relevance To the best of our knowledge, we describe a detailed clinical characterization of the largest CD cohort carrying the TGFBI p.(L558P) variant. We propose that the atypical phenotype of this recently reported alteration can be classified as a form of LCD type IV. The results show that OCT and anterior‐posterior analysis of the stromal location of the opacities, along with a genetic analysis of TGFBI, are required to ensure accurate diagnosis and management of CDs.

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“…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

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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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Late-Onset Lattice Corneal Dystrophy Without Typical Lattice Lines Caused by a Novel Mutation in the TGFBI Gene

Cited by 13 publications

References 25 publications

pH Induced Conformational Transitions in the Transforming Growth Factor β-Induced Protein (TGFβIp) Associated Corneal Dystrophy Mutants

pH Induced Conformational Transitions in the Transforming Growth Factor β-Induced Protein (TGFβIp) Associated Corneal Dystrophy Mutants

Transforming growth factor beta‐induced p.(L558P) variant is associated with autosomal dominant lattice corneal dystrophy type IV in a large cohort of Spanish patients

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

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