Pathogenesis and treatments of TGFBI corneal dystrophies

Corneal dystrophies are a group of inherited disorders localized to various layers of the cornea that affect corneal transparency and visual acuity. The deposition of insoluble protein materials in the form of extracellular deposits or intracellular cysts is pathognomic. Mutations in TGFBI are responsible for superficial and stromal corneal dystrophies. The gene product, transforming growth factor β induced protein (TGFBIp) accumulates as insoluble deposits in various forms. The severity, clinicopathogenic variations, age of the onset, and location of the deposits depend on the type of amino acid alterations in the protein. Until 2006, 38 different pathogenic mutants were reported for the TGFBI-associated corneal dystrophies. This number has increased to 63 mutants, reported in more than 30 countries. There is no effective treatment to prevent, halt, or reverse the deposition of TGFBIp. This review presents a complete mutation update, classification of phenotypes, comprehensive reported incidents of various mutations, and current treatment options and their shortcomings. Future research directions and possible approaches to inhibiting disease progression are discussed.

Clinical and genetic aspects of the TGFBI-associated corneal dystrophies.

Purpose To analyze human transforming growth factor b-induced (TGFBI) gene mutations in Chinese patients with corneal dystrophies (CDs). Methods Twenty-one families with corneal dystrophies were subjected to phenotypic and genotypic characterization. The corneal phenotypes of patients were documented by slit lamp photography. Mutation screening of the coding regions of TGFBI was performed by direct sequencing. An additional 43 families and 3 sporadic patients with TGFBI dystrophies from China reported in the literature were reviewed. Results Five mutations of TGFBI were identified in 21 families with CDs, including one novel small deletion mutation, c.delta1838-1849 (p.Delta613-616VAEP), responsible for one variant lattice CD (LCD) family and 4 known mutations, R555W mutation for 10 granular cornea dystrophy type I (GCD1) families, R124H for 5 GCD type II (GCD2), R124C for 4 LCD1, and H626R for one variant LCD. In a cohort of Chinese patients (n=355) with TGFBI dystrophies from 64 families and 3 sporadic cases, 19 distinct mutations were found in several different CD subtypes. The 3 most common phenotypes were ranked as follows: GCD1, GCD2, and LCD1. Mutation hot spots at R124 and R555 occurred in >80% of these families. Conclusions Our findings extend the mutational spectrum of TFGBI, and this is also the first extensively delineated TGFBI mutation profile associated with the various corneal dystrophies in the Chinese population.

Analysis of TGFBI gene mutations in Chinese patients with corneal dystrophies and review of the literature.

Human transforming growth factor β-induced (TGFBI), is a gene responsible for various corneal dystrophies. TGFBI produces a protein called TGFBI, which is involved in cell adhesion and serves as a recognition sequence for integrins. An alteration in cell surface interactions could be the underlying cause for the progressive accumulation of extracellular deposits in different layers of the cornea with the resulting changes of refractive index and transparency. To this date, 69 different pathogenic or likely pathogenic variants in TGFBI have been identified in a heterozygous or homozygous state in various corneal dystrophies, including a novel variant reported here. All disease-associated variants were inherited as autosomal-dominant traits but one; this latter was inherited as an autosomal recessive trait. Most corneal dystrophy-associated variants are located at amino acids Arg124 and Arg555. To keep the list of corneal dystrophy-associated variant current, we generated a locus-specific database for TGFBI (http://databases.lovd.nl/shared/variants/TGFBI) containing all pathogenic and likely pathogenic variants reported so far. Non-disease-associated variants are described in specific databases, like gnomAD and ExAC but are not listed here. This article presents the most recent up-to-date list of disease-associated variants.

/pdf/mutation-update-tgfbi-pathogenic-and-likely-pathogenic-1ladd4l6mw.pdf

Mutation update: TGFBI pathogenic and likely pathogenic variants in corneal dystrophies.

Assessment of Confocal Microscopy for the Diagnosis of Polymerase Chain Reaction-Positive Acanthamoeba Keratitis: A Case-Control Study.

Objective To analyze transforming growth factor β–induced ( TGFBI ) gene mutations in 2 Chinese families with Thiel-Behnke corneal dystrophy (TBCD). Methods Forty-five individuals in 2 Chinese families with TBCD were examined using slitlamp biomicroscopy. Genomic DNA was extracted from peripheral leukocytes of affected and unaffected family members. Molecular genetic analysis of the TGFBI gene was performed using polymerase chain reaction and standard automated sequencing methods. Results In 17 family members with TBCD, an Arg124Cys (R124C) mutation of the TGFBI gene was identified, whereas the Arg555Gln (R555Q) mutation was absent. The Arg124Cys mutation was absent in all unaffected individuals. Conclusions The Arg124Cys mutation was associated with TBCD in 2 Chinese families. This mutation in the TGFBI gene may induce different phenotypes of corneal dystrophy. Clinical Relevance Thiel-Behnke corneal dystrophy may be caused by an Arg124Cys mutation of the TGFBI gene.

https://jamanetwork.com/journals/jamaophthalmology/articlepdf/423237/eog80008_641_644.pdf

Arg124Cys mutation of the TGFBI gene in 2 Chinese families with Thiel-Behnke corneal dystrophy.

Clinical and experimental findings in Acanthamoeba keratitis with Heidelberg Retina Tomograph III-RCM.

To cope with the strong vibration of a supporting structure excited by external loads under operating conditions, and in order to achieve the purpose of vibration reduction by structural optimization through modal modification, a modal modification method was proposed, through structural vibration theory. Subsequently, the search performance of an improved particle swarm optimization method was analyzed before conducting a case study on the structural optimization. Finally, aiming at the problem of strong vibration of gun mount at the time of firing, a finite element model of the gun mount was constructed and the type and natural frequency of the gun vibration in a free state was analyzed. Meanwhile, taking the thickness, height and width of the stiffening structure of the bracket as the design variables, combined with the improved particle swarm algorithm, an optimized mathematical model was developed with the first-order natural frequency of the gun mount as the objective function. The secondary development of Abaqus finite element software by using Python is used as a tool to calculate the optimization model. By virtue of optimation, thickness, width and height of the stiffening structure are 156.4mm, 453.7mm and 238.9mm at the range of [100,600]mm, [100,700]mm, [100,700]mm, respectively, and the base frequency of the gun mount has been increased by 11.3%. The effect is remarkable. doi: 10.5829/ije.2022.35.04a.14

Modal Optimization Design of Supporting Structure Based on the Improved Particle Swarm Algorithm

OBJECTIVE
To observe the clinical efficacy on improving the quality of meibum in patients suffer from dry eye disease (DED) due to meibomian gland dysfunction (MGD) with hyperactivity ofdue todeficiency pattern after being treated with Pinggan Yuyin Qingre formula (, PGYYQR).


METHODS
Totally 120 patients who met the inclusion criteria were included and stratified into three levels according to the level of MGD (1-3), and patients in each level was randomly allocated into the treatment group and control group according to a 1∶1 ratio. Both groups were treated with sodium hyaluronate eye drops, and the treatment group was also given PGYYQR granules. Both groups were treated continuously for eight weeks. The score of the properties of meibomian gland (MG) secretion, the score of the palpebral margins, the average noninvasive tear breakup time (NITBUTav), lipid layer thickness (LLT), and Traditional Chinese Medicine (TCM) syndrome efficacy were compared between the two groups after treatment.


RESULTS
A total of 116 cases were included in the statistical analysis. The differences were statistically significant in the score of the properties of MG secretion, the score of the palpebral margins, and NITBUTav between the two groups after treatment, the treatment group was superior to the control group; there was no evidence of a difference in LLT. In terms of TCM syndrome efficacy, the total effective rate was 84.7% in the treatment group and 50.9% in the control group, with the statistically significant difference. None of the included cases had adverse reactions.


CONCLUSIONS
PGYYQR is effective in improving the quality of meibum, and the tear film stability which thereby relieving the ocular symptoms in MGD-related DED patients with hyperactivity ofdue todeficiency pattern.

Dry eye disease due to meibomian gland dysfunction treated with Pinggan Yuyin Qingre formula: a stratified randomized controlled trial.

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Papers

Arg124Cys mutation of the TGFBI gene in 2 Chinese families with Thiel-Behnke corneal dystrophy.

Clinical and experimental findings in Acanthamoeba keratitis with Heidelberg Retina Tomograph III-RCM.

Modal Optimization Design of Supporting Structure Based on the Improved Particle Swarm Algorithm

Dry eye disease due to meibomian gland dysfunction treated with Pinggan Yuyin Qingre formula: a stratified randomized controlled trial.