Granular Corneal Dystrophy Type Research Articles

Morphological Characteristics of Granular Corneal Dystrophy Type 1 in the Korean Population

Purpose: Granular corneal dystrophy type 1 (GCD1) is a genetic disorder characterized by grayish-white granular deposits in the corneal stroma, typically manifesting before age 10. The specific characteristics of GCD1 in the Korea population remain insufficiently described. This study investigated the morphological features of GCD1 corneas with confirmed genetic mutations in this population.Methods: Medical records of GCD1 patients with the R555W mutation confirmed through transforming growth factor β induced (TGFBI) gene testing on oral epithelium or blood samples from 2005-2022, were analyzed. Corneal photographs obtained using a slit lamp biomicroscope were also examined.Results: The study group included 11 males and 19 females with an average age of 35.7 years, ranging from 3-70 years. All participants were heterozygotes. In 28 individuals (56 eyes, representing 93.3% of the total), there were signs of corneal deposit detachments, known as “drop-off”, observed in patients aged 6 years and above. Surface deposits reemerged at the peripheral margin of previous locations and expanded toward the center. The number and shape of opacities significantly changed with age, showing cycles of deposition and shedding. There were variations in the severity of opacities within the same family, particularly with advancing age, and distinct opacities extending into deeper stromal layers.Conclusions: This study outlines the morphological characteristics of corneas in Korean GCD1 patients, based on corneal photograph analysis. These findings provide a basis for future comparative studies with GCD2 and may aid rapid clinical diagnosis based on clinical findings, prior to genetic testing confirmation.

Mini-Review: Clinical Features and Management of Granular Corneal Dystrophy Type 2.

Granular corneal dystrophy type 2 (GCD2) is an autosomal dominant corneal stromal dystrophy that is caused by p.Arg124His mutation of transforming growth factor β induced (TGFBI) gene. It is characterized by well demarcated granular shaped opacities in central anterior stroma and as the disease progresses, extrusion of the deposits results in ocular pain due to corneal epithelial erosion. Also, diffuse corneal haze which appears late, causes decrease in visual acuity. The prevalence of GCD2 is high in East Asia including Korea. Homozygous patients show a severe phenotype from an early age, and the heterozygote phenotype varies among patients, depending on several types of compound heterozygous TGFBI mutations. In the initial stage, conservative treatments such as artificial tears, antibiotic eye drops, and bandage contact lenses are used to treat corneal erosion. Different surgical methods are used depending on the depth and extent of the stromal deposits. Phototherapeutic keratectomy removes anterior opacities and is advantageous in terms of its applicability and repeatability. For deeper lesions, deep anterior lamellar keratoplasty can be used as the endothelial layer is not always affected. Recurrence following these treatments are reported within a wide range of rates in different studies due to varying definition of recurrence and follow-up period. In patients who have undergone corneal laser vision-correction surgeries such as photorefractive keratectomy, LASEK, or LASIK including SMILE surgery, corneal opacity exacerbates rapidly with severe deterioration of visual acuity. Further investigations on new treatments of GCD2 are necessary.

Visual Function after Multifocal Intraocular Lens Insertion in a Heterozygous Granular Corneal Dystrophy Type 2 Patient: Case Report

Purpose: A patient with heterozygous granular corneal dystrophy type 2 (GCD2) underwent phacoemulsification with multifocal intraocular lens insertion, and complained of visual discomfort. We investigated the cause of the discomfort and visual function in this case.Case summary: A 59-year-old woman with granular opacity had slit lamp photographs taken 5 years earlier. Two years later, she underwent phacoemulsification with multifocal intraocular lens (Trifocal AT Lisa tri toric 839MP<sup>®</sup>, Carl Zeiss Meditec AG, Inc., Jena, Germany) insertion in both eyes at a local clinic. She felt very uncomfortable after the surgery, but the granular and lattice opacities due to GCD2 of her corneas remained stationary for 5 years. Her visual acuity decreased from preoperatively (preoperative: right 0.5, left 0.6; last visit: right 0.3, left 0.4). Her contrast sensitivity was also decreased and the total higher order aberration was increased (right 1.590 μm, left 1.194 μm), compared to normal range.Conclusions: Multifocal intraocular lens insertion in cataract surgery can lead to severe declines in contrast sensitivity and visual acuity and increased higher-order aberration in a GCD2 patient. It may not be advisable to use multifocal intraocular lenses in a GCD2 patient.

Sequential Custom Therapeutic Keratectomy for the Treatment of Granular Corneal Dystrophy Type 1: A Long-term Study.

To evaluate the effectiveness of sequential custom phototherapeutic keratectomy (SCTK) for granular corneal dystrophy type 1 (GCD1). Thirty-seven eyes of 21 patients with GCD1 were treated with SCTK to remove superficial opacifications, regularize the corneal surface, and decrease optical aberrations. SCTK is a sequence of custom therapeutic excimer laser keratectomies with step-by-step intraoperative corneal topography monitoring of results. Six eyes of 5 patients previously treated with penetrating keratoplasty received SCTK for disease recurrence. Pre-operative and postoperative corrected distance visual acuity (CDVA), refractive values, mean pupillary keratometry, and pachymetry were retrospectively analyzed. The mean follow-up period was 41.3 months. SCTK provided significant decimal CDVA improvement, from 0.33 ± 0.22 to 0.63 ± 0.24 (P < .0001) at the last available follow-up visit. One eye, initially treated with penetrating keratoplasty, showed visually significant disease 8 years after the first SCTK and was re-treated. Mean corneal pachymetry difference between preoperative and final follow-up values was 78.42 ± 62.26 µm. Mean corneal curvature and the spherical component did not show a statistically significant change or hyperopic shift. Astigmatism and higher order aberration reduction were statistically significant. SCTK is a powerful tool for the treatment of anterior corneal pathologies hindering vision and quality of life, such as GCD1. SCTK is less invasive and fosters more rapid visual recovery than penetrating keratoplasty or deep anterior lamellar keratoplasty. Providing significant visual improvement, SCTK can be the preferred initial treatment in eyes with GCD1. [J Refract Surg. 2023;39(6):422-429.].

Reduced OPA1, Mitochondrial Fragmentation and Increased Susceptibility to Apoptosis in Granular Corneal Dystrophy Type 2 Corneal Fibroblasts.

The progressive degeneration of granular corneal dystrophy type 2 (GCD2) corneal fibroblasts is associated with altered mitochondrial function, but the underlying mechanisms are incompletely understood. We investigated whether an imbalance of mitochondrial dynamics contributes to mitochondrial dysfunction of GCD2 corneal fibroblasts. Transmission electron microscopy revealed several small, structurally abnormal mitochondria with altered cristae morphology in GCD2 corneal fibroblasts. Confocal microscopy showed enhanced mitochondrial fission and fragmented mitochondrial tubular networks. Western blotting revealed higher levels of MFN1, MFN2, and pDRP1 and decreased levels of OPA1 and FIS1 in GCD2. OPA1 reduction by short hairpin RNA (shRNA) resulted in fragmented mitochondrial tubular networks and increased susceptibility to mitochondrial stress-induced apoptosis. A decrease in the mitochondrial biogenesis-related transcription factors NRF1 and PGC1α was observed, while there was an increase in the mitochondrial membrane proteins TOM20 and TIM23. Additionally, reduced levels of mitochondrial DNA (mtDNA) were exhibited in GCD2 corneal fibroblasts. These observations suggest that altered mitochondrial fission/fusion and biogenesis are the critical molecular mechanisms that cause mitochondrial dysfunction contributing to the degeneration of GCD2 corneal fibroblasts.

Comparison of the Predictive Accuracy of Intraocular Lens Power Calculations after Phototherapeutic Keratectomy in Granular Corneal Dystrophy Type 2.

Granular corneal dystrophy type 2 (GCD2) is an autosomal dominant disease affecting vision. Phototherapeutic keratectomy (PTK) is advantageous in removing vision-threatening corneal opacities and postponing keratoplasty; however, it potentially disturbs accurate intraocular lens (IOL) power calculation in cataract surgery. The myopic/hyperopic Haigis-L method with or without the central island has been reported; nevertheless, an optimal method has not yet been established. To compare the predictive accuracy of post-PTK IOL power calculations in GCD2, the retrospective data of 30 eyes from July 2017 to December 2020 were analyzed. All GCD2-affected eyes underwent post-PTK standard cataract surgery using the WaveLight EX500 platform (Alcon Laboratories, Inc., Fort Worth, TX, USA) under a single surgeon. The mean prediction error (MPE) and absolute error (MAE) with the myopic/hyperopic Haigis-L, Barrett Universal II, Barrett True-K, Haigis, and SRK/T by standard keratometry (K) and total keratometry (TK), where possible, were analyzed. Barrett Universal II and SRK/T showed significantly superior MPE, and MAE compared with the myopic/hyperopic Haigis-L method. TK was not significantly superior to K in the same formula. In conclusion, this study suggests that these biometries and formulas, especially Barrett Universal II and SRK/T, are potentially useful in IOL power calculation in GCD2 after PTK.

Granular Corneal Dystrophy Type 2 in a Middle-aged Male

Granular Corneal Dystrophy Type 2 in a Middle-aged Male

Phenotypes of Granular Corneal Dystrophy Type 2 among Koreans in Their Twenties

Purpose: Granular corneal dystrophy type 2 (GCD2) is a hereditary disease that features granular and lattice stromal deposits in the cornea. There are homozygotes and heterozygotes and the opacities are exacerbated by corneal trauma or surgery, such as laser in situ keratomileusis (LASIK). As there is individual variability in GCD2 phenotypes, we investigated various corneal features of GCD2 patients in their twenties, the main age group for refractive surgery.Methods: From genetically confirmed GCD2 patients who had an R124H mutation of the transforming growth factor β induced (&lt;i&gt;TGFBI&lt;/i&gt;) gene at age 20 to 29 years, we chose representative patients: one homozygote; one compound heterozygote; one simple heterozygote with a severe phenotype with many granular deposits; one common heterozygote; and four heterozygotes with normal corneas. The corneas of all patients were subject to slit-lamp examination and photographed.Results: The homozygote had confluent granular deposits covering the cornea. The compound heterozygote had granular and lattice deposits covering the center of the cornea. The patient with a severe phenotype had more than 30 granular deposits in one eye, but was a simple GCD2 heterozygote, verified by full-sequencing of the &lt;i&gt;TGFBI&lt;/i&gt; gene. In the four patients with normal corneas, a single small lesion was subsequently detected during follow-up in two, at 3 weeks and 6 months, respectively. Both corneas were judged clear at chance examinations.Conclusions: Among Koreans in their twenties, GCD2 patients have various phenotypes, from clear corneas to severe confluent opacities. There are GCD2 heterozygotes with nearly clear corneas, so caution must be taken when choosing patients for refractive surgery.

Assessment of the corneal biomechanical features of granular corneal dystrophy type 2 using dynamic ultra-high-speed Scheimpflug imaging.

To evaluate the corneal biomechanical features of eyes with granular corneal dystrophy type 2 (GCD2) by analyzing corneal biomechanical indices obtained using a Corvis ST (CST) dynamic ultra-high-speed Scheimpflug imaging device. In this retrospective case-control study, 35 CST parameters were compared in normal eyes (control) and eyes of patients with GCD2 treated at Osaka University Hospital, Osaka, Japan. The parameters included the Corvis Biomechanical Index (CBI), which is important in differentiating eyes with keratoconus from normal eyes. We measured the deposition rates of lesions in the central 7-mm region of the eye and assessed the correlation between the deposition rate and the CBI. Twenty-one eyes with GCD2 and 23 control eyes were analyzed. Eyes with GCD2 showed significantly less corneal stiffness in 15 CST parameters than did control eyes. In particular, the CBI was remarkably higher in eyes with GCD2 than in control eyes (P = 0.000006). Additionally, the deposition rate and the CBI were positively correlated. GCD2 eyes had softer corneas than did control eyes in most biomechanical CST parameters, and one of the parameters (the CBI) was linked to the rate of deposited lesions. Since IOP may be underestimated in GCD2 eyes, management should be especially careful in GCD2 cases complicated by glaucoma.

Contrast Sensitivity Changes after Phototherapeutic Keratectomy in Heterozygote Granular Corneal Dystrophy Type 2

Purpose: Contrast sensitivity, the ability to distinguish the relative difference in luminance of an object from its surrounding or adjacent objects, is a useful measure of visual function. In granular corneal dystrophy type 2 (GCD2), opacity of the corneal stroma causes deterioration in visual function. We compared the contrast sensitivity of GCD2 patients before and after phototherapeutic keratectomy (PTK) to evaluate the perioperative visual function in these patients.Methods: This study included 22 eyes of heterozygote GCD2 patients. The visual acuity and contrast sensitivity were measured before and after PTK. The contrast sensitivity was measured in mesopic and photopic background luminances, with glare (G) levels of 0-2 (G0, G1, and G2, respectively) and spatial frequencies at 1.5, 3, 6, 12, and 18 cycles per degree (cpd).Results: The contrast sensitivity increased after PTK at 1.5 and 3 cpd in mesopic and photopic conditions with G0-2 glare (p &lt; 0.05). At 6 cpd, the contrast sensitivity increased in the mesopic condition with G1 glare, and in the photopic condition with G0-2 glare (p &lt; 0.05). However, there was no change in contrast sensitivity at any glare level at 12 and 18 cpd after PTK.Conclusions: In GCD2 patients, the contrast sensitivity increased significantly after PTK. The vision of GCD2 patients, which is decreased due to corneal opacity, is improved after PTK.

Atypical conjunctival hyaline deposition in a case of granular corneal dystrophy type 2

A 43-year-old woman diagnosed with granular corneal dystrophy (GCD) type 2 on the basis of bilateral granular deposition in the corneal stroma (Fig. 1A) and the detection of a heterozygous R124H mutation of the transforming growth factor–β–induced gene (TGFIB) presented with ocular pain and conjunctival hyperemia in her left eye. Slitlamp examination showed swelling and congestion of the left conjunctiva associated with yellowish-white deposits in the bulbar region (Fig. 1B). Two weeks later, similar conjunctival lesions appeared in the lower portion of her right eye.

Mutation effects on FAS1 domain 4 based on structure and solubility

Mutations in the fasciclin 1 domain 4 (FAS1–4) of transforming growth factor β-induced protein (TGFBIp) are associated with insoluble extracellular deposits and corneal dystrophies (CDs). The decrease in solubility upon mutation has been implicated in CD; however, the exact molecular mechanisms are not well understood. Here, we performed molecular dynamics simulations followed by solvation thermodynamic analyses of the FAS1–4 domain and its three mutants—R555W, R555Q, and A546T—linked to granular corneal dystrophy type 1, Thiel-Behnke corneal dystrophy and lattice corneal dystrophy, respectively. We found that both R555W and R555Q mutants have less affinity toward solvent water relative to the wild-type protein. In the R555W mutant, a remarkable increase in solvation free energy was observed because of the structural changes near the mutation site. The mutation site W555 is buried in other hydrophobic residues, and R557 simultaneously forms salt bridges with E554 and D561. In the R555Q mutant, the increase in solvation free energy is caused by structural rearrangements far from the mutation site. R558 separately forms salt bridges with D575, E576, and E598. Thus, we thus identified the relationship between the decrease in solubility and conformational changes caused by mutations, which may be useful in designing potential therapeutics and in blocking FAS1 aggregation related to CD.

Long-Term Observation of Deep Anterior Lamellar Keratoplasty in Patients with Post-LASIK Granular Corneal Dystrophy Type 2: Two Case Reports

IntroductionLaser-assisted in situ keratomileusis (LASIK) exacerbates granular corneal dystrophy type 2. Post-LASIK granular corneal dystrophy type 2 is treated by several surgical techniques. To the best of our knowledge, no report has addressed the results of deep anterior lamellar keratoplasty in affected patients. Here, we report our experience regarding deep anterior lamellar keratoplasty treatment of patients with post-LASIK granular corneal dystrophy type 2.MethodsWe describe two Japanese women who underwent deep anterior lamellar keratoplasty to treat corneal opacities that worsened after LASIK.ResultsOne patient had a family history of corneal dystrophies. During the initial visit to our clinic, numerous fine opacities were found at the LASIK flap interface in both patients. The clinical findings were compatible with post-LASIK granular corneal dystrophy type 2. Both patients underwent deep anterior lamellar keratoplasty by one of the authors (T.C.). In both procedures, the surgeon used a visco-dissection technique and successfully removed the whole corneal stroma. Histopathological examination of the excised corneal button from each eye revealed amyloid and hyaline deposits at the LASIK flap interface. Neither patient experienced recurrent corneal opacity during the follow-up visit at 8 years (patient 1) and 6 years (patient 2).ConclusionDeep anterior lamellar keratoplasty can be used for the treatment of post-LASIK granular corneal dystrophy type 2. Removal of the entire host stroma may be important for the prevention of recurrent corneal opacity.

Compound heterozygous mutations in TGFBI cause a severe phenotype of granular corneal dystrophy type 2

We investigated the clinical and genetic features of patients with severe phenotype of granular corneal dystrophy type 2 (GCD2) associated with compound heterozygosity in the transforming growth factor-β-induced (TGFBI) gene. Patients with severe GCD2 underwent ophthalmic examination (best-corrected visual acuity test, intraocular pressure measurement, slit-lamp examination, and slit-lamp photograph analysis) and direct Sanger sequencing of whole-TGFBI. The patient’s family was tested to determine the pedigrees. Five novel mutations (p.(His174Asp), p.(Ile247Asn), p.(Tyr88Cys), p.(Arg257Pro), and p.(Tyr468*)) and two known mutations (p.(Asn544Ser) and p.(Arg179*)) in TGFBI were identified, along with p.(Arg124His), in the patients. Trans-phase of TGFBI second mutations was confirmed by pedigree analysis. Multiple, extensive discoid granular, and increased linear deposits were observed in the probands carrying p.(Arg124His) and other nonsense mutations. Some patients who had undergone phototherapeutic keratectomy experienced rapid recurrence (p.(Ile247Asn) and p.(Asn544Ser)); however, the cornea was well-maintained in a patient who underwent deep anterior lamellar keratoplasty (p.(Ile247Asn)). Thus, compound heterozygosity of TGFBI is associated with the phenotypic variability of TGFBI corneal dystrophies, suggesting that identifying TGFBI second mutations may be vital in patients with extraordinarily severe phenotypes. Our findings indicate the necessity for a more precise observation of genotype–phenotype correlation and additional care when treating TGFBI corneal dystrophies.

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

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.

A recognition survey of granular corneal dystrophy type 2 genetic detection in China.

To evaluate the feasibility of promoting genetic detection for granular corneal dystrophy type 2 (GCD2) by a questionnaire conducted among citizens in five cities in China. The data were collected by questionnaire, and analyzed by Chi-square test and one-tailed t test in IBM SPSS statistics. Based on the survey data on the awareness of GCD2 genetic detection in this study and the positive predictive analysis report of the citizens in five cities in China, the vast majority (84.2%) of respondents had never heard of it and did not know that GCD2 patients have been prohibited from performing excimer surgery that can deteriorate GCD2 patients' condition even leading to blindness. Though 3.4% of patients understood GCD2 very much, they have no idea that GCD2 could not be 100% accuracy diagnosed by the conventional inspection methods. It is feasible and necessary to use GCD2 genetic detection as an excimer preoperative examination project. In order to promote the development of detection project, a few improvements should be carried out in terms of the promoting efforts, costs, and research progress.

A pathogenic variant in the transforming growth factor beta I (TGFBI) in four Iranian extended families segregating granular corneal dystrophy type II: A literature review.

Objective(s):Granular and lattice corneal dystrophies (GCDs & LCDs) are autosomal dominant inherited disorders of the cornea. Due to genetic heterogeneity and large genes, unraveling the mutation is challenging.Materials and Methods:Patients underwent comprehensive clinical examination, and targeted next-generation sequencing (NGS) was used for mutation detection. Co-segregation and in silico analysis was accomplished.Results:Patients suffered from GCD. NGS disclosed a known pathogenic variant, c.371G>A (p.R124H), in exon 4 of TGFBI. The variant co-segregated with the phenotype in the family. Homozygous patients manifested with more severe phenotypes. Variable expressivity was observed among heterozygous patients. Conclusion:The results, in accordance with previous studies, indicate that the c.371G>A in TGFBI is associated with GCD. Some phenotypic variations are related to factors such as modifier genes, reduced penetrance and environmental effects.

Autophagy modulation in animal models of corneal diseases: a systematic review.

Autophagy is an intracellular catabolic process implicated in the recycling and degradation of intracellular components. Few studies have defined its role in corneal pathologies. Animal models are essential for understanding autophagy regulation and identifying new treatments to modulate its effects. A systematic review (SR) was conducted of studies employing animal models for investigations of autophagy in corneal diseases. Studies were identified using a structured search strategy (TS = autophagy AND cornea*) in Web of Science, Scopus, and PubMed from inception to September 2019. In this study, 230 articles were collected, of which 28 were analyzed. Mouse models were used in 82% of the studies, while rat, rabbit, and newt models were used in the other 18%. The most studied corneal layer was the epithelium, followed by the endothelium and stroma. In 13 articles, genetically modified animal models were used to study Fuch endothelial corneal dystrophy (FECD), granular corneal dystrophy type 2 (GCD2), dry eye disease (DED), and corneal infection. In other 13 articles, animal models were experimentally induced to mimic DED, keratitis, inflammation, and surgical scenarios. Furthermore, in 50% of studies, modulators that activated or inhibited autophagy were also investigated. Protective effects of autophagy activators were demonstrated, including rapamycin for DED and keratitis, lithium for FECD, LYN-1604 for DED, cysteamine and miR-34c antagomir for damaged corneal epithelium. Three autophagy suppressors were also found to have therapeutic effects, such as aminoimidazole-4-carboxamide-riboside (AICAR) for corneal allogeneic transplantation, celecoxib and chloroquine for DED.

Lysosomal dysfunction of corneal fibroblasts underlies the pathogenesis of Granular Corneal Dystrophy Type 2 and can be rescued by TFEB.

Granular corneal dystrophy type 2 (GCD2) is the most common form of transforming growth factor β‐induced (TGFBI) gene‐linked corneal dystrophy and is pathologically characterized by the corneal deposition of mutant‐TGFBIp. The defective autophagic degradation of pathogenic mutant‐TGFBIp has been shown in GCD2; however, its exact mechanisms are unknown. To address this, we investigated lysosomal functions using corneal fibroblasts. Levels of cathepsins K and L (CTSK and CTSL) were significantly decreased in GCD2 cells, but of cathepsins B and D (CTSB and CTSD) did not change. The maturation of the pro‐enzymes to their active forms (CTSB, CTSK and CTSL) was inhibited in GCD2 cells. CTSL enzymes directly degraded both LC3 (autophagosomes marker) and mutant‐TGFBIp. Exogenous CTSL expression dramatically reduced mutant‐TGFBIp in GCD2 cells, but not TGFBIp in WT cells. An increased lysosomal pH and clustered lysosomal perinuclear position were found in GCD2 cells. Transcription factor EB (TFEB) levels were significantly reduced in GCD2 cells, compared to WT. Notably, exogenous TFEB expression improved mutant‐TGFBIp clearance and lysosomal abnormalities in GCD2 cells. Taken together, lysosomal dysfunction in the corneal fibroblasts underlies the pathogenesis of GCD2, and TFEB has a therapeutic potential in the treatment of GCD2.

Protein Analysis of the TGFBIR124H Mouse Model Gives Insight into Phenotype Development of Granular Corneal Dystrophy.

Mutations in the transforming growth factor β-induced protein (TGFBIp) are associated with TGFBI-linked corneal dystrophies, which manifests as protein deposits in the cornea. A total of 70 different disease-causing mutations have been reported so far including the common R124H substitution, which is associated with granular corneal dystrophy type 2 (GCD2). The disease mechanism of GCD2 is not known and the current treatments only offer temporary relief due to the reoccurrence of deposits. The corneal protein profiles of the three genotypes (wild-type (WT), heterozygotes, and homozygotes) of a GCD2 mouse model are compared using label-free quantitative LC-MS/MS. The mice do not display corneal protein deposits and the global protein expression between the three genotypes is highly similar. However, the expression of mutated TGFBIp is 41% of that of the WT protein. It is proposed that the lowered expression level of mutant TGFBIp protein relative to WT protein is the direct cause of the missing development of corneal deposits in the mouse. The overall protein profiles of the corneas are not impacted by the reduced amount of TGFBIp. Altogether, this supports a partial reduction in mutated TGFBIp as a potential treatment strategy for GCD2.