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Schnyder Corneal Dystrophy

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Schnyder Corneal Dystrophy. Core disease mechanisms, molecular and cellula...

2026-08-09
Asta MONDO:0007374 Model: Asta Scientific Corpus Retrieval 17 citations

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Schnyder Corneal Dystrophy. Core disease mechanisms, molecular and cellula...

This report is retrieval-only and is generated directly from Asta results.

  • Papers retrieved: 17
  • Snippets retrieved: 20

Relevant Papers

[1] Case Report of Schnyder Corneal Dystrophy—A Rare Lipid Metabolic Disorder of the Cornea

  • Authors: N. Stoyanova, Abdulrahman Imran, Zain Hassan, K. Kraev, Y. Basheva-Kraeva et al.
  • Year: 2025
  • Venue: Life
  • URL: https://www.semanticscholar.org/paper/332581b42c2eac358549c406f695a6774dd24f64
  • DOI: 10.3390/life15030409
  • PMID: 40141754
  • PMCID: 11943904
  • Summary: This case illustrates the diagnostic challenges of SCD, particularly in the absence of corneal crystals, a hallmark feature that is not universally present, and highlights the need for multidisciplinary care in SCD management.
  • Evidence snippets:
  • Snippet 1 (score: 0.599) > Schnyder corneal dystrophy (SCD) is a rare, progressive autosomal dominant disorder that was first described by the Swiss ophthalmologist Franz Schnyder in 1924 [1][2][3]. It has a prevalence estimated at less than 1 in 1,000,000 individuals. It is characterized by bilateral opacification of the cornea due to abnormal accumulation of lipids, primarily cholesterol and phospholipids, within the corneal stroma (Figure 1) [4]. This lipid deposition leads to progressive corneal clouding and visual impairment, often beginning in early adulthood and advancing with age [5]. Clinically, SCD is notable for its variable presentation, ranging from subtle stromal haze to conspicuous crystalline deposits, depending on the stage and severity of the disease [6,7]. > tion leads to progressive corneal clouding and visual impairment, often beginning in early adulthood and advancing with age [5]. Clinically, SCD is notable for its variable presentation, ranging from subtle stromal haze to conspicuous crystalline deposits, depending on the stage and severity of the disease [6,7]. > The genetic basis of SCD was elucidated in 2007, with the identification of mutations in the UBIAD1 gene as the primary causative factor. UBIAD1 encodes a key enzyme that is involved in cholesterol metabolism and vitamin K2 biosynthesis, underscoring the metabolic underpinnings of the disease [8]. However, the exact molecular mechanisms linking UBIAD1 mutations to corneal lipid accumulation remain poorly understood. Dysregulated lipid metabolism is thought to impair corneal transparency, leading to progressive visual decline [9][10][11]. > While traditionally considered a corneal disorder, SCD is increasingly recognized for its potential systemic implications, including dyslipidemia. Advances in imaging modalities, such as optical coherence tomography (OCT) and confocal microscopy, have enhanced the diagnostic accuracy, particularly in cases lacking visible corneal crystals.
  • Snippet 2 (score: 0.453) > Case Report of Schnyder Corneal Dystrophy—A Rare Lipid Metabolic Disorder of the Cornea
  • Snippet 3 (score: 0.430) > Advances in imaging modalities, such as optical coherence tomography (OCT) and confocal microscopy, have enhanced the diagnostic accuracy, particularly in cases lacking visible corneal crystals. Despite these advancements, treatment options remain limited, with penetrating keratoplasty being reserved for advanced cases [11][12][13][14][15]. > This case underscores the importance of recognizing rare corneal dystrophies such as SCD, particularly in patients with systemic comorbidities or atypical corneal findings. Enhanced clinical awareness and improved diagnostic strategies could facilitate earlier diagnosis, timely management, and better visual outcomes for affected individuals. The genetic basis of SCD was elucidated in 2007, with the identification of mutations in the UBIAD1 gene as the primary causative factor. UBIAD1 encodes a key enzyme that is involved in cholesterol metabolism and vitamin K2 biosynthesis, underscoring the metabolic underpinnings of the disease [8]. However, the exact molecular mechanisms linking UBIAD1 mutations to corneal lipid accumulation remain poorly understood. Dysregulated lipid metabolism is thought to impair corneal transparency, leading to progressive visual decline [9][10][11]. > While traditionally considered a corneal disorder, SCD is increasingly recognized for its potential systemic implications, including dyslipidemia. Advances in imaging modalities, such as optical coherence tomography (OCT) and confocal microscopy, have enhanced the diagnostic accuracy, particularly in cases lacking visible corneal crystals. Despite these advancements, treatment options remain limited, with penetrating keratoplasty being reserved for advanced cases [11][12][13][14][15]. > This case underscores the importance of recognizing rare corneal dystrophies such as SCD, particularly in patients with systemic comorbidities or atypical corneal findings. Enhanced clinical awareness and improved diagnostic strategies could facilitate earlier diagnosis, timely management, and better visual outcomes for affected individuals. > Life 2025, 15, 409 3 of 8

[2] An Arg124His mutation in TGFBI associated to Avellino corneal dystrophy in a Chinese pedigree

  • Authors: Zhensheng Gu, Peiquan Zhao, G. He, C. Wan, Gang Ma et al.
  • Year: 2011
  • Venue: Molecular Vision
  • URL: https://www.semanticscholar.org/paper/1a83983671140b413929af8e0f143bf0554b6023
  • PMID: 22194646
  • PMCID: 3244477
  • Citations: 9
  • Summary: This study demonstrated that a G>A transition in Arg124His of TGFBI was responsible for Avellino corneal dystrophy in a Chinese pedigree, which further supports the importance of T GFBIp in maintaining transparency of the cornea.
  • Evidence snippets:
  • Snippet 1 (score: 0.570) > The challenge to ophthalmologists and researchers is to correctly diagnose and classify corneal dystrophies, as well as to understand their phenotype-genotype aspects. In 2008, a useful nomenclature for corneal dystrophies was established by the International Committee on the Classification of Corneal dystrophies (IC3D) based on traditional clinical examination and advances in molecular genetics. Under the IC3D classification system, each dystrophy has a detailed description including an OMIM number, eponyms, genetic loci, relevant genes, onset, signs, symptoms, histopathology, etc., combining clinical features and genetic characteristics including molecular mechanism and protein functions [5][6][7]. > In this study, we recruited a Chinese four-generation pedigree affected by corneal dystrophy and identified the gene mutation responsible for the disease. We hope our study will provide an insight into the mechanisms of the disease.

[3] Atypical Regressive Corneal Endothelial Cysts in Long-Term Confocal Follow-Up

  • Authors: A. Smedowski, E. Wylęgała, L. Wójcik, D. Tarnawska
  • Year: 2015
  • Venue: Medicine
  • URL: https://www.semanticscholar.org/paper/6b567579bbf916d4f69a5a083f090f5e7dba4b0d
  • DOI: 10.1097/MD.0000000000000564
  • PMID: 25738472
  • PMCID: 4553953
  • Summary: The presented case is an example of an unusual corneal endothelial syndrome with probably nondystrophic background due to observed dynamic state with regressive tendency.
  • Evidence snippets:
  • Snippet 1 (score: 0.548) > T he term ''dystrophy'' is commonly used to describe an inherited disorder, fulfilling certain criteria. In ophthalmology, the term ''corneal dystrophy'' has no strictly defined borders. It is a group of corneal disorders usually with the following features: inherited, noninflammatory, typically bilateral, symmetric, slowly progressive (regression in dystrophy development is unusual), and without relationship to environmental or systemic factors. 1 However, in some cases corneal dystrophies can coexist with other systemic disabilities (macular dystrophy or amyloidosis, which is often called lattice dystrophy type II, Schnyder dystrophy) or can develop unilateral (posterior polymorphous endothelial dystrophy). On the other hand, there are some corneal abnormalities which are excluded from the corneal dystrophies group, despite fulfilling defined conditions (such as ''cornea plana''-inherited, bilateral, usually not related to systemic abnormalities). 2 Corneal endothelial dystrophies concern diseases characterized by corneal endothelial cells layer abnormalities, what usually leads to slowly progressive degeneration of corneal endothelium, decreasing of cells density and affecting visual acuity. 3 n the contrary, there are nondystrophic endothelial syndromes that include variants of iridocorneal endothelial syndromes (ICE) and endothelial (preendothelial) deposits. In such cases, changes might be observed unilaterally with tendency for both progression and regression while they are secondary pronunciation of other eye disorders (inflammatory changes, iris and iridocorneal angle pathologies, iatrogenic repercussion). 4,5 he aim of this report is to describe abnormal phenotype of corneal endothelium in a 36-year-old patient, with features of clinical regression accompanied by progressive endothelial pathology.

[4] Evaluation of the Genetic Variation Spectrum Related to Corneal Dystrophy in a Large Cohort

  • Authors: Wei Li, N. Qu, Jian-kang Li, Yu-Xin Li, Dong Han et al.
  • Year: 2021
  • Venue: Frontiers in Cell and Developmental Biology
  • URL: https://www.semanticscholar.org/paper/e08001759aede393322d1ef0f4e90cc8d18ccb36
  • DOI: 10.3389/fcell.2021.632946
  • PMID: 33816482
  • PMCID: 8012530
  • Citations: 12
  • Influential citations: 1
  • Summary: The genetic landscape and mutation spectrum of patients with corneal dystrophies (CDs) in a large Han ethnic Chinese Cohort with inherited eye diseases (IEDs) is characterized and the variation spectrum of 22 CD-related genes is systematically described.
  • Evidence snippets:
  • Snippet 1 (score: 0.509) > Corneal dystrophies (CDs) are genetically heterogeneous disorders characterized by the gradual accumulation of deposits within different corneal layers, resulting in changes in corneal transparency and refractive index (Bron, 1990). > Clinically, these diseases are divided into anatomical categories according to the specific corneal layer involved. According to the current International Committee for Classification of Corneal Dystrophies (IC3D), CDs can be divided into 4 categories and 22 subcategories. CDs can classify into one of the following anatomical categories (Weiss et al., 2008(Weiss et al., , 2015)): (a) epithelial and subepithelial CDs; (b) epithelial-stromal transforming growth factor-beta-induced protein (TGFBI) CDs; (c) stromal CDs; and (d) endothelial CDs. At present, corneal transplants are the most effective method for the treatment of CDs. Due to lack of clinical symptoms, some patients may be misdiagnosed before phototherapeutic keratectomy (PTK) treatment or neglected before refractive surgery, which highlights the urgent need to understand the disease mechanism of CDs (Zeng et al., 2017). > Genetically, CDs are autosomal dominant, autosomal recessive or X-linked modes. Autosomal dominant inheritance accounts for most cases and is accompanied by a high degree of penetrance (Pieramici and Afshari, 2006). To date, studies have identified disease-causing mutations in 18 genes associated with CDs, many of which have established genotype-phenotype associations.
  • Snippet 2 (score: 0.456) > To date, studies have identified disease-causing mutations in 18 genes associated with CDs, many of which have established genotype-phenotype associations. For example, mutations in six genes (CHST6, OMIM 605294; UBIAD1, OMIM 611632; SLC4A11, OMIM 610206; PIKFYVE, OMIM 609414; TACSTD2, OMIM 137290; DCN, and OMIM 125255) have found a direct genetic association with macular corneal dystrophies (MCD), Schnyder CD (SCD), congenital hereditary endothelial dystrophy (CHED), fleck CD (FCD), gelatinous drop-like CD (GDLD), and congenital stromal CD (CSCD), respectively, (Zhang et al., 2013). At the same time, there are significant heterogeneities in distinct mutations of the same gene. For instance, according to the second edition of IC3D, five distinct TGFBI mutations (p.R124H, p.R555W, p.R124C, p.R555Q, and p.R124L) cause different types of CDs, including Granular corneal dystrophy, type 2; Granular corneal dystrophy, type 1; Lattice corneal dystrophy, type 1 (LCD1); Thiel-Behnke corneal dystrophy (TBCD); and Reis-Bücklers corneal dystrophy, respectively, (Weiss et al., 2008(Weiss et al., , 2015)). > Panel-based targeted exon sequencing has proven to have excellent performance in the molecular diagnosis of heterogeneous genetic diseases. Studies have confirmed that targeted enrichment based on multi-gene panels are highly sensitive, accurate, and reproducible (Adams and Eng, 2018). A comprehensive overview of the genetic landscape associated with the CD phenotype have been provided based on sequencing hundreds of potentially related disease-causing genes.

[5] Case report: A case of corneal deposits between binocular descemet membrane and corneal endothelial layer after small-incision lenticule extraction (SMILE) followed by HPV vaccine

  • Authors: Hao Zhang, Yingping Deng, Ke Ma, Chengshu Sun, Jing Tang
  • Year: 2022
  • Venue: Frontiers in Medicine
  • URL: https://www.semanticscholar.org/paper/0789d476b0e8b9ba5ee04537e6b64258a801025c
  • DOI: 10.3389/fmed.2022.1042405
  • PMID: 36619641
  • PMCID: 9811408
  • Summary: There are two possible causes of corneal changes in patients: the first is IGA elevation caused by vaccination, deposited in the cornea, and the ARSG gene mutation of the patient leads to a potential congenital corneAL dystrophy, and clinical manifestations occur under the stimulation of the vaccine.
  • Evidence snippets:
  • Snippet 1 (score: 0.505) > There are currently two kinds of reported diseases of congenital corneal dystrophy similar to the corneal changes in our case. > (1) Schnyder corneal dystrophy disease (SCD). The clinical characteristics of SCD are the deposition of cholesterol and phospholipids in the subepithelium and in the stroma of the cornea, resulting in corneal opacity (10)(11)(12)(13). The specific clinical manifestations are as follows: (1) It is an autosomal dominant genetic disease with a high degree of extrinsic dominance, so there is often a family history ( 14). ( 2) The disease usually starts at about 20 years old, and a few can be 10 years younger (15). ( 3) Often binocular disease, the degree of corneal turbidity increases with age, so the vision is progressive decline, there may be glare and photophobia (16). ( 4) Limbal lipid opacity resembles cornea arcus senilis (16). ( 5) About 54% of SCD patients had crystalline deposition of cholesterol in the cornea ( 16). ( 6) About 4% of SCD patients have genu valgus, spinal and finger malformations and other signs. ( 7) About 66% of SCD patients had dyslipidemia (16-19). ( 8) The pathogenesis of SCD may be related to local lipid metabolism defects caused by UBIADI gene mutation, but the exact mechanism is not clear (11, 13, 14). ( 2) Pre-descemet corneal dystrophy (PDCD) is a rare form of stromal dystrophy of the cornea characterized by dense, irregular deposits of opaque material between the deep stromal layer and the descemet membrane and associated with mutations in the STS gene (20). PDCD has several subgroups, which may represent sporadic, age-related, or degenerative changes (21). The symptoms of PDCD patients are mild, and their vision is generally not affected (22).

[6] Pathogenesis and treatments of TGFBI corneal dystrophies.

  • Authors: K. Han, Seung-Il Choi, Tae-im Kim, Yong-Sun Maeng, R. Stulting et al.
  • Year: 2016
  • Venue: Progress in retinal and eye research
  • URL: https://www.semanticscholar.org/paper/4133399eafb3c6754d8fb5fba5de42f66fc2b5cd
  • DOI: 10.1016/j.preteyeres.2015.11.002
  • PMID: 26612778
  • Citations: 107
  • Influential citations: 10
  • Summary: The current knowledge of TGFBI corneal dystrophies including clinical manifestations, epidemiology, most common and recently reported associated mutations for each disease, and treatment modalities are summarized.
  • Evidence snippets:
  • Snippet 1 (score: 0.501) > Transforming growth factor beta-induced (TGFBI) corneal dystrophies are a group of inherited progressive corneal diseases. Accumulation of transforming growth factor beta-induced protein (TGFBIp) is involved in the pathogenesis of TGFBI corneal dystrophies; however, the exact molecular mechanisms are not fully elucidated. In this review article, we summarize the current knowledge of TGFBI corneal dystrophies including clinical manifestations, epidemiology, most common and recently reported associated mutations for each disease, and treatment modalities. We review our current understanding of the molecular mechanisms of granular corneal dystrophy type 2 (GCD2) and studies of other TGFBI corneal dystrophies. In GCD2 corneal fibroblasts, alterations of morphological characteristics of corneal fibroblasts, increased susceptibility to intracellular oxidative stress, dysfunctional and fragmented mitochondria, defective autophagy, and alterations of cell cycle were observed. Other studies of mutated TGFBIp show changes in conformational structure, stability and proteolytic properties in lattice and granular corneal dystrophies. Future research should be directed toward elucidation of the biochemical mechanism of deposit formation, the relationship between the mutated TGFBIp and the other materials in the extracellular matrix, and the development of gene therapy and pharmaceutical agents.

[7] Update on the genetics of corneal endothelial dystrophies

  • Authors: C. Kannabiran, S. Chaurasia, Muralidhar Ramappa, V. Mootha
  • Year: 2022
  • Venue: Indian Journal of Ophthalmology
  • URL: https://www.semanticscholar.org/paper/3080a90259e7d8e711648196c9dbb44611bdc589
  • DOI: 10.4103/ijo.IJO_992_22
  • PMID: 35791103
  • PMCID: 9426112
  • Citations: 17
  • Summary: Knowledge of the genetics of corneal endothelial dystrophies has considerably advanced within the last decade and has contributed to better diagnosis of these dystrophic diseases as well as opened up the possibility of novel therapeutic approaches based on the molecular mechanisms involved.
  • Evidence snippets:
  • Snippet 1 (score: 0.485) > Many recent advances in the genetics of corneal endothelial dystrophies have brought to light pathways and mechanisms underlying the development of these diseases and pointed to correlations between genotype and phenotype. Despite a high degree of genetic heterogeneity, particularly for PPCD and FECD, the prevalence of mutations in the existing genes are rapidly being defined in patients from different regions. The application of genome sequencing may further facilitate the identification of new loci or novel types of pathogenic changes in existing genes in the near future and enhance our understanding of the underlying genetics of these diseases. A significant corollary of the new developments in the field lies in the possibility of developing suitable new therapies for these disorders based on their known genetic and molecular mechanisms. Proof of concept has already been obtained for using specific approaches to inhibit the triplet repeat expansionmediated disease pathways in FECD. Genetic screening may aid in establishing a genotype-phenotype correlation for patients. In a majority of cases, a meticulous slit-lamp examination and histological analysis wherever available help in determining the exact nature of the endothelial disease, although a diagnosis in patients with unusual manifestations can be supported by genetic testing. In familial forms of PPCD, knowing the mutation can aid in early screening and detection of affected but asymptomatic individuals. Developments in genetics have improved our knowledge of the corneal endothelial dystrophies and reduced the inaccuracies in their nomenclature. An accurate diagnosis of the specific type of endothelial dystrophy assists in planning the most appropriate management strategy and prognostication of the clinical condition. Furthermore, with the advent of alternatives such as pharmacotherapy and targeted molecular therapy in the management of endothelial dystrophies, a precise diagnosis of the clinical phenotype has become increasingly paramount.

[8] Ocular Involvement in Hereditary Amyloidosis

  • Authors: A. Minnella, R. Rissotto, E. Antoniazzi, M. Di Girolamo, M. Luigetti et al.
  • Year: 2021
  • Venue: Genes
  • URL: https://www.semanticscholar.org/paper/760dd2f506df9afdd3db36a6fd1ce28bd189aaf1
  • DOI: 10.3390/genes12070955
  • PMID: 34206500
  • PMCID: 8304974
  • Citations: 64
  • Summary: This review aims at describing the main biochemical, histopathological and clinical features of systemic amyloidosis associated with eye involvement, with particular emphasis on the inherited forms.
  • Evidence snippets:
  • Snippet 1 (score: 0.480) > The role of KE gene mutations in human chromosome 5q31 has been unequivocally established by molecular genetics as causative for corneal dystrophies, but nevertheless, the pathogenic mechanisms responsible for abnormal protein aggregation still need to be clarified [100]. > The molecular analysis of KE-related corneal dystrophies revealed deposits of abnormal protein in the forms of amyloid fibrils and/or nonamyloid amorphous aggregations. > Population analyses have revealed two hot spots for mutations, Arg-124 and Arg-555, associated with corneal dystrophies. In the Arg-124 mutation, four different mutations give rise to four different phenotypes. The Arg124Cys mutation has been linked with lattice corneal dystrophy type 1, granular corneal dystrophy type 2, granular corneal dystrophy type 3 and a variant of granular corneal dystrophy type 1 [100]. > Mutations of KE cause hereditary corneal dystrophies that are characterized by the abnormal deposition of amyloid fibrils and/or granular aggregation in the cornea and have been linked to at least 13 clinically and histopathologically distinct autosomal dominant corneal dystrophies. Amyloid deposits are found in many corneal dystrophies, including lattice dystrophy (LCD) type I, IA, II, IIIA, IIIB, IV, V, VI and VII and granular dystrophy type II, also called Avellino dystrophy [99]. > Regarding differential diagnosis, along with the primary amyloid deposits, a variety of ocular diseases can develop secondary amyloid deposits, namely trachoma, lepra, sarcoidosis, interstitial keratitis, phlyctenular keratitis, uveitis, chronic post-traumatic inflammation, glaucoma, keratoconus and retinopathy of prematurity. Recently, point mutations in the transforming growth factor-β-induced gene (TGFBI) encoding for the protein KE have been found to be associated with these corneal diseases [99].

[9] The Sociodemographic and Risk Factors for Fuchs’ Endothelial Dystrophy: A Nationwide, Matched Case–Control Study in Taiwan

  • Authors: Yuh-Shin Chang, Chung‐Han Ho, Jhi-Joung Wang, S. Tseng, Ren-Long Jan
  • Year: 2022
  • Venue: Journal of Personalized Medicine
  • URL: https://www.semanticscholar.org/paper/3aa8aeb16188d0d89b3d5083336df4ba1c705bb7
  • DOI: 10.3390/jpm12020305
  • PMID: 35207793
  • PMCID: 8877330
  • Citations: 2
  • Summary: It is found that more than half of the FED patients in Taiwan were aged ≥45 years old, there was an equal female-to-male ratio (1.06:1), and patients with a lower income and living in northern Taiwan had higher odds of developing FED.
  • Evidence snippets:
  • Snippet 1 (score: 0.464) > Fuchs' corneal endothelial dystrophy (FED), the most common form of corneal dystrophy, affects the endothelium, which is the innermost layer of the cornea. FED is characterized by endothelial cell density reduction with endothelium cell morphology alterations including variation in cell shape, known as cellular pleomorphism, and variation in the cell size, known as polymegathism [1]. FED usually presents in the fifth decade of life and progresses over the next two to three decades with continued endothelium cell loss and dysfunction. Some FED patients may be asymptomatic in the early stages of the disease, but patients may have glare or reduced visual acuity, severe pain due to the corneal edema progression to stromal thickness, increased bulla formation, or even long-standing corneal vascularization [2]. > FED is a multifactorial disorder caused by a complex combination of genetic, biochemistry, biology, and environmental factors. The pathophysiology of FED remains unknown, although several proposed mechanisms have been reported [1,[3][4][5]. Channelopathy, related to mutations in the genes of the ion channels in the corneal endothelium appears to be an important pathogenetic factor in the development of FED [3,4]. Elevation of oxidative stress and reactive oxygen species accumulation could lead to apoptosis of endothelial cells and is also regarded as one major cause of the development of FED [1,4]. The epithelialmesenchymal transition, in which fibroblastic or epithelial cell phenotypes transform from endothelial cells, could result in the secretion of extracellular matrix proteins leading to abnormal deposition, is thought to be involved in the pathogenesis of FED [1,4,5]. > The estimated incidence and prevalence of FED varies greatly worldwide, with a higher prevalence in Europe and the USA and lower rates in Asia, possibly because of different genetic or environmental factors and a difference in clinical definitions of FED [6,7]. Being older than 40 years of age is a major risk factor for FED development [4,5,8].

[10] Genetic mutations and molecular mechanisms of Fuchs endothelial corneal dystrophy

  • Authors: Xue Liu, Tao Zheng, Chuchu Zhao, Yi Zhang, Hanruo Liu et al.
  • Year: 2021
  • Venue: Eye and Vision
  • URL: https://www.semanticscholar.org/paper/12e7cdcdc924d1fde2012ef77fd55d89c3d6957d
  • DOI: 10.1186/s40662-021-00246-2
  • PMID: 34130750
  • PMCID: 8204469
  • Citations: 26
  • Influential citations: 2
  • Summary: The mutations of COL8A2, TCF4 , TCF8 , SLC4A11 and AGBL1 genes in Fuchs endothelial corneal dystrophy are summarized and several potential treatments related to the pathogenesis of Fuchs vascular disease are discussed.
  • Evidence snippets:
  • Snippet 1 (score: 0.456) > Background Fuchs endothelial corneal dystrophy is a hereditary disease and the most frequent cause of corneal transplantation in the worldwide. Its main clinical signs are an accelerated decrease in the number of endothelial cells, thickening of Descemet’s membrane and formation of guttae in the extracellular matrix. The cornea’s ability to maintain stromal dehydration is impaired, causing painful epithelial bullae and loss of vision at the point when the amount of corneal endothelial cells cannot be compensated. At present, apart from corneal transplantation, there is no other effective treatment that prevents blindness. Main text In this review, we first summarized the mutations of COL8A2 , TCF4 , TCF8 , SLC4A11 and AGBL1 genes in Fuchs endothelial corneal dystrophy. The molecular mechanisms associated with Fuchs endothelial corneal dystrophy, such as endoplasmic reticulum stress and unfolded protein response pathway, oxidative stress, mitochondrial dysregulation pathway, apoptosis pathway, mitophagy, epithelial-mesenchymal transition pathway, RNA toxicity and repeat-associated non-ATG translation, and other pathogenesis, were then explored. Finally, we discussed several potential treatments related to the pathogenesis of Fuchs endothelial corneal dystrophy, which may be the focus of future research. Conclusions The pathogenesis of Fuchs endothelial corneal dystrophy is very complicated. Currently, corneal transplantation is an important method in the treatment of Fuchs endothelial corneal dystrophy. It is necessary to continuously explore the pathogenesis of Fuchs endothelial corneal dystrophy and establish the scientific foundations for the development of next-generation corneal therapeutics.

[11] Systematic Ocular Phenotyping of Knockout Mouse Lines Identifies Genes Associated With Age-Related Corneal Dystrophies

  • Authors: Andrew Briere, P. Vo, Benjamin Yang, David J. Adams, Takanori Amano et al.
  • Year: 2025
  • Venue: Investigative Ophthalmology & Visual Science
  • URL: https://www.semanticscholar.org/paper/ff217a6c3bd93ff3465693742f74ebdd4ef549f3
  • DOI: 10.1167/iovs.66.5.7
  • PMID: 40323269
  • PMCID: 12060066
  • Citations: 1
  • Summary: This study identified 14 genes linked to LACD in knockout mice, 12 of which are novel in corneal biology and may serve as potential therapeutic targets for treating corneal diseases in aging human populations.
  • Evidence snippets:
  • Snippet 1 (score: 0.451) > Purpose This study investigates genes contributing to late-adult corneal dystrophies (LACDs) in aged mice, with potential implications for late-onset corneal dystrophies (CDs) in humans. Methods The International Mouse Phenotyping Consortium (IMPC) database, containing data from 8901 knockout mouse lines, was filtered to include late-adult mice (49+ weeks) with significant (P < 0.0001) CD phenotypes. Candidate genes were mapped to human orthologs using the Mouse Genome Informatics group, with expression analyzed via PLAE and a literature review for prior CD associations. Comparative analyses of LACD genes from IMPC and established human CD genes from IC3D included protein interactions (STRING), biological processes (PANTHER), and molecular pathways (KEGG). Results Analysis identified 14 genes linked to late-adult abnormal corneal phenotypes. Of these, 2 genes were previously associated with CDs in humans, while 12 were novel. Seven of the 14 genes (50%) were expressed in the human cornea based on single-cell transcriptomics. Protein–protein interactions via STRING showed several significant interactions with known human CD genes. PANTHER analysis identified six biological processes shared with established human CD genes. Two genes (Rgs2 and Galnt9) were involved in pathways related to human corneal diseases, including cGMP-PKG signaling, mucin-type O-glycan biosynthesis, and oxytocin signaling. Other candidates were implicated in pathways such as pluripotency of stem cells, MAPK signaling, WNT signaling, actin cytoskeleton regulation, and cellular senescence. Conclusions This study identified 14 genes linked to LACD in knockout mice, 12 of which are novel in corneal biology. These genes may serve as potential therapeutic targets for treating corneal diseases in aging human populations.

[12] Systematic ocular phenotyping of 8,707 knockout mouse lines identifies genes associated with abnormal corneal phenotypes

  • Authors: P. Vo, Denise M. Imai-Leonard, Benjamin Yang, Andrew Briere, Andy Shao et al.
  • Year: 2025
  • Venue: BMC Genomics
  • URL: https://www.semanticscholar.org/paper/27f14f70a1aee24427e12604879b43dd4ad247ab
  • DOI: 10.1186/s12864-025-11222-8
  • PMID: 39833678
  • PMCID: 11744888
  • Citations: 3
  • Summary: This study identified 213 mouse genes that resulted in statistically significant abnormal corneal phenotypes in knockout mice, many of which have not previously been implicated in corneal pathology, and identified other possible underappreciated mechanisms relevant to the human cornea.
  • Evidence snippets:
  • Snippet 1 (score: 0.450) > Corneal dysmorphologies (CDs) are typically classified as either regressive degenerative corneal dystrophies (CDtrs) or defective growth and differentiation-driven corneal dysplasias (CDyps). Both eye disorders have multifactorial etiologies. While previous work has elucidated many aspects of CDs, such as presenting symptoms, epidemiology, and pathophysiology, the genetic mechanisms remain incompletely understood. The purpose of this study was to analyze phenotype data from 8,707 knockout mouse lines to identify new genes associated with the development of CDs in humans. 8,707 knockout mouse lines phenotyped by the International Mouse Phenotyping Consortium were queried for genes associated with statistically significant (P < 0.0001) abnormal cornea morphology to identify candidate CD genes. Corneal abnormalities were investigated by histopathology. A literature search was used to determine the proportion of candidate genes previously associated with CDs in mice and humans. Phenotypes of human orthologues of mouse candidate genes were compared with known human CD genes to identify protein-protein interactions and molecular pathways using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), Protein Analysis Through Evolutionary Relationships (PANTHER), and Kyoto Encyclopedia of Genes and Genomes. Analysis of data from 8,707 knockout mouse lines identified 213 candidate CD genes. Of these, 37 (17%) genes were previously known to be associated with CD, including 14 in the mouse, 16 in humans, and 7 in both. The remaining 176 (83%) genes have not been previously implicated in CD. We also searched publicly available RNAseq data and found that 131 of the total 213 (61.5%) were expressed in adult human corneal tissue. STRING analysis showed several interactions within and between candidate and established CD proteins. All cellular pathways of the established genes were found in the PANTHER analysis of the candidate genes. Several of the candidate genes were implicated in corneal disease, such as TGF-ß signaling. We also identified other possible underappreciated mechanisms relevant to the human cornea. We identified 213 mouse genes that resulted in statistically significant abnormal corneal phenotypes in knockout mice, many of which have not

[13] TGFBI gene mutation analysis in a Chinese pedigree of Reis-Bücklers corneal dystrophy

  • Authors: Ke Ma, Guo Liu, Yin Yang, Man Yu, R. Sui et al.
  • Year: 2010
  • Venue: Molecular Vision
  • URL: https://www.semanticscholar.org/paper/a22756ae29fd2c344106a9957ef100cd6084cb04
  • PMID: 20360992
  • PMCID: 2847680
  • Citations: 15
  • Summary: The R124C mutation in TGFBI is also found to be responsible for RBCD, along with G623D and R124L, which is a known mutation for lattice corneal dystrophy type I.
  • Evidence snippets:
  • Snippet 1 (score: 0.450) > Corneal dystrophy is a group of diseases with autosomal dominant inheritance.Until now, corneal dystrophies failed to be clearly classified because of the variability in phenotypic expression of the diseases.A proposed corneal dystrophy classification system, which is identical or similar to those in the current nomenclature, is anatomically based with dystrophies classified according to the layer mainly involved, such as the epithelial and subepithelial, Bowman's layer, stroma, Descemet's membrane, and endothelium [16].Clinical characteristics such as the depth of the cornea affected, the morphology of the deposits, and the histopathological features are also important for classifying different corneal dystrophies [17].However, dystrophies with overlapping and atypical characteristics are still too similar to be distinguished from one another.A Chinese family with atypical RBCD was recently reported [14].This family presented with a unique corneal dystrophy within the Bowman's layer and the corneal stroma.However, no lattice was noted in the proband or other affected members, and the deposits were located in the mid-stroma of the cornea, which was different from the phenotypes previously reported in lattice corneal dystrophy patients with R124C mutation.Some corneal dystrophies affect multiple corneal layers and therefore cannot be classified as a single type based on morphologic criteria. > Phenotypically, the pedigree we documented here exhibited typical features of RBCD.The affected individuals presented with a gray-white geographic opacity in the anterior to mid-stroma of both eyes.In addition, geometric and round opacities in the subepithelial layers and anterior to mid-stroma were found in all of the affected family members.The clinical features, including recurrent erosion and gradually developing opacities of the Bowman's layer, were consistent with the characteristic of RBCD [1,18] and to those found in the families previously described by Afshari et al. [10] and Aldave et al. [19].

[14] Corneal cell therapy: with iPSCs, it is no more a far-sight

  • Authors: Koushik Chakrabarty, R. Shetty, Arkasubhra Ghosh
  • Year: 2018
  • Venue: Stem Cell Research & Therapy
  • URL: https://www.semanticscholar.org/paper/5528565bd93ce92ce3b62c947ccbaec04a2c8d3a
  • DOI: 10.1186/s13287-018-1036-5
  • PMID: 30359313
  • PMCID: 6202849
  • Citations: 64
  • Influential citations: 1
  • Summary: This review discusses and summarizes protocols that have been devised so far to direct differentiation of human pluripotent stem cells (hPSCs) to different corneal cell phenotypes and intends to facilitate an understanding which would allow developing efficient and robust protocols to obtain specific cornean cell phenotype from hPSCs.
  • Evidence snippets:
  • Snippet 1 (score: 0.445) > Subsequently, Utheim et al. [22] found that storage temperature also affects the gene expression pattern of the cultured human oral keratinocytes. Here, it is crucial to note that the authors observed storage temperature influencing the expression of genes involved in both the proliferation and differentiation process of oral keratinocytes extending its significance in the field. The lower survival rate of the transplanted oral epithelia in the corneal limbal regions [19] is further accentuated by the duration of storage of cultured LESCs and oral keratinocytes limiting its availability for repeat transplants which is often necessary to address some of the LESC-related corneal surface diseases. These challenges can be addressed using iPSCs which can be stored effectively upon their generation and directed to LESCs and CEC phenotype when required. Efforts towards obtaining LESCs from iPSCs have provided good results [24] thereby placing iPSCs as a promising source of transplantable LESCs. Another common affliction of the cornea is the corneal dystrophies (CD) which typically have a genetic etiology [25] and often with no options for therapy other than keratoplasty in advanced cases. Corneal diseases such as the dystrophies are a persisting global health concern with a significant economic burden since there are very limited drug-based treatments available. In addition, there are problems of graft rejection, or the transplanted tissue also being affected with the disease as the underlying cause for the pathology has not been addressed. However, for many of the CDs, the cellular signaling mechanisms involved in their pathology are still elusive. Although studies [26] have demonstrated the formation and accumulation of the mutated gene products (proteins) in most of the corneal dystrophies, little is known about the contextual molecular mechanisms involved in the formation of such deposits. Therefore, understanding the cellular context and relevant mechanisms involved in corneal dystrophy is imperative for identifying possible therapeutic interventions. Differentiation protocols continue to improve leading to robust generation of corneal cells from iPSCs, thereby providing the necessary platform to model the corneal diseases and its utilization in cell replacement therapy.

[15] Macular dystrophies associated with Stargardt-like phenotypes

  • Authors: R. A. S. Amaral, Olivia Araújo Zin, M. V. Salles, F. Motta, J. Sallum
  • Year: 2023
  • Venue: Arquivos Brasileiros de Oftalmologia
  • URL: https://www.semanticscholar.org/paper/87b1b56d8b2886a9853c330997c5e59ddf505221
  • DOI: 10.5935/0004-2749.2021-0415
  • PMID: 36995812
  • PMCID: 11619082
  • Citations: 2
  • Summary: Macular dystrophies may have phenotypic similarities to Stargardt-like phenotype associated with other genes besides the classic ones, and these genes may be associated with pathogenic variants related to the phenotypes.
  • Evidence snippets:
  • Snippet 1 (score: 0.435) > The pharmacological modulation of the visual cycle serves as a novel approach to the potential treatment of degenerative retinal diseases. Finding the involved genes in the phenotypes leads to new possibilities of discovering treatments by increasing or decreasing the function on the metabolic pathways of those genes. As the pathophysiology of STGD1 is complex, a multitargeted approach could help in the identification of alternative pathways or modification factors involving the disease mechanism. > In this report of four patients with macular dystrophy and history suggesting Stargardt-like disease, two patient's phenotypes were related to AD genes (RIMS1 and CRX) and those of the other two patients were related to AR genes (CRB1 and RDH12). STGD1 is the most common inherited macular dystrophy but has a wide clinical spectrum, and several inherited macular dystrophies have phenotypic similarities that can make clinical diagnosis challenging. As the disease progress, clinical appearance may change over time, and its end-stage appearance of diffuse atrophy and peripheral involvement are almost indistinguishable from each other. Functional tests are still important for the characterization of the phenotype and help in the diagnostic definition, especially in cone dystrophies, which are often the main differential diagnosis for STGD1. > Molecular genetic studies and detailed clinical descriptions have demonstrated that a central atrophic lesion with surrounding subretinal yellow flecks can arise secondary to mutations in different genes. With the improvement of potential treatments for inherited retinal dystrophies, correct molecular diagnosis is essential.

[16] New therapeutic targets in rare genetic skeletal diseases

  • Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
  • Year: 2015
  • Venue: Expert Opinion on Orphan Drugs
  • URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
  • DOI: 10.1517/21678707.2015.1083853
  • PMID: 26635999
  • PMCID: 4643203
  • Citations: 39
  • Influential citations: 1
  • Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
  • Evidence snippets:
  • Snippet 1 (score: 0.426) > However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e. chondrocyte) to the abnormal extracellular environment is also important for disease progression as illustrated by several GSDs discussed in this review. > It is important that 'omics'-based approaches and technologies are systematically applied to the study of rare GSDs so that definitive reference profiles and disease signatures are generated for each phenotype. These can then be used in a Systems Biology approach to identify both common and dissimilar pathological signatures and disease mechanisms. This approach is entirely dependent upon relevant in vitro and in vivo models (and also novel 'disease-mechanism phenocopies' [107]) for testing new diagnostic and prognostic tools and for determining the molecular mechanisms that underpin the pathophysiology so that effective therapeutic treatments can be developed and validated. This approach will eventually lead to personalized treatments and care strategies centred on shared disease mechanisms with the use of relevant biomarkers to monitor the efficacy of treatment and disease progression. > It is vital that all relevant stakeholders are involved from the outset in defining the appropriate outcomes of any potential therapeutic regime. The perceptions of a successful therapy can differ widely between the clinical academic community and the relevant patient-support groups and it is vital that there is engagement on all these issues. > In summary, the identification of causative genes and mutations for GSDs over the last 20 years, coupled with the generation and in-depth analysis of a plethora of relevant cell and mouse models, has derived new knowledge on disease mechanisms and suggested potential therapeutic targets. The fast-evolving hypothesis that clinically disparate diseases can share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.

[17] Identification of potential therapeutic target SPP1 and related RNA regulatory pathway in FECD through bioinformatics

  • Authors: Fuji Deng, Zhixiang Yan, Jinpeng Li, Long-Fei Wu, Yong Liu et al.
  • Year: 2026
  • Venue: iScience
  • URL: https://www.semanticscholar.org/paper/05c568392b6bdfd8f9e49f9f4cb0da6c906f6a89
  • DOI: 10.1016/j.isci.2026.115591
  • PMID: 42028016
  • PMCID: 13099362
  • Summary: It is proposed that SPP1 is a potential biomarker and therapeutic target for FECD, and the NEAT1/miR-181b-5p/SPP1 axis might be a regulatory RNA pathway involved in FECD development.
  • Evidence snippets:
  • Snippet 1 (score: 0.426) > Corneal blindness is the second leading cause of blindness globally, severely impacting the quality of life for tens of millions of people. Among the numerous corneal diseases, Fuchs' endothelial corneal dystrophy (FECD) is a common, age-related, and progressive posterior corneal disorder with a strong hereditary predisposition. 1 Its core pathophysiology is the functional failure of corneal endothelial cells (CECs). CECs form a non-regenerative monolayer on the posterior surface of the cornea and precisely regulate corneal stromal hydration through their ''pump-leak'' mechanism, thereby maintaining corneal transparency. 2 n patients with FECD, CEC density progressively declines, and cells exhibit morphological abnormalities (pleomorphism, polymegathism), accompanied by the formation of characteristic extracellular matrix (ECM) deposits known as guttae on Descemet's membrane. 3 The eventual loss of CEC function leads to stromal edema, decreased corneal transparency, and ultimately, severe vision loss. 4,5 tiological studies have revealed a highly complex genetic background for FECD. The abnormal expansion of a CTG trinucleotide repeat in an intron of the TCF4 gene is the most common and significant genetic risk factor. 6,7 Additionally, pathogenic mutations discovered in genes such as SLC4A11, ZEB1, and COL8A2 have provided important clues. 8,9 However, a critical knowledge gap remains: how are these upstream genetic variations translated into complex downstream cellular pathologies? Specifically, how do they drive CECs to undergo endothelial-tomesenchymal transition (EndMT), a process where CECs lose their epithelial characteristics and acquire mesenchymal properties, which is widely considered a core mechanism in guttae formation and corneal fibrosis 3 ? > Currently, no FDA-approved targeted drug is available globally that can effectively delay or reverse the course of the disease. 4 herefore, identifying and validating new therapeutic targets that can intervene in the disease process has become a pressing clinical need.

Notes

  • This provider combines search_papers_by_relevance with snippet_search.
  • No synthesis or second-stage model call is performed.