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Pedigree of the Chinese family with dominant GCD. Affected men and women are indicated by filled squares and circles, respectively. Normal individuals are shown as empty symbols. Proband is indicated with arrow
Source publication
Purpose:
This study is to summarize the concurrent keratoconus (KC) and granular corneal dystrophy (GCD) phenotype and identify the underlying genetic cause in a 23-year-old male patient.
Methods:
A detailed family history and clinical data from the patient and his parents were collected by ophthalmologic examination. The candidate genes were ca...
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Corneal cross-linking (CXL) is aimed at halting the progression of keratoconus and is widely considered to be the golden standard in its treatment. It is usually contraindicated, however, in patients with corneal thickness of less than 400 µm, leaving the ophthalmic surgeon no option, but to perform transepithelial CXL (epi-on), usually regarded as...
As the primary indication for corneal transplantation, the pathogenesis of keratoconus remains elusive. Aiming to identify whether any mutation from extracellular-matrix (ECM)-related genes contributes to the patients with sporadic cases of keratoconus (KC) from Chinese Han population, one hundred and fifty-three participants in total were enrolled...
Introduction:
Keratoconus (KC), is a bilateral, noninflammatory degenerative disease of the cornea which is characterized by progressive corneal ectasia and loss of visual function. The onset of KC is commonly seen at puberty and affects approximately 1 in 2000 in the general population.
Objective:
The aim of this study was to assess the clinica...
Corneal Cross-linking (CXL) is aimed at halting the progression of keratoconus and is widely considered to be the golden standard technique in the treatment of this disease. It is usually contraindicated, however, in patients with less than 400 µm of corneal thickness, leaving the ophthalmic surgeon with the option of performing Transepithelial CXL...
Citations
... Variant in KRT82 has been identified as hotspot mutation in sporadic microsatellite-instable colorectal cancers (38). Studies have identified a correlation between other keratin gene and KC (39,40), but there existed no reports indicating a relationship of KRT82 with ocular diseases. NSUN5 is a cytosine-5 RNA methyltransferase which was selectively expressed in radial glial cells during embryonic cortex (41). ...
Purpose
Keratoconus (KC) is a corneal ectasia disease with complex genetic heterogeneity. The present study aimed to identify susceptibility genes in Chinese patients with KC.
Methods
Exome sequencing (ES) was performed in 28 Chinese KC patients to search for susceptibility genes of the disease. The candidate variants were filtered out by multi-step bioinformatics analysis and validated by Sanger sequencing. Another 100 individuals with KC were also recruited to verify those variants by Sanger sequencing.
Results
By filtering out nonsynonymous variants located in exon, selecting variants which were presented in two or more samples and applying public databases to remove common variants, along with the inclusion of missense SNVs located in differential expressed genes and protein damaging variants (stop gain/stop loss SNVs and InDels), we have identified 6 SNVs (4 missense SNVs: c.1168 T > C in TRANK1, c.341A>T in ERMP1, c.4346 T > C in SDK2, c.1730A>C in COL6A1; 2 stop gain SNVs: c.1138 C > T in CNBD1, c.241 C > T in KRT82) and 2 InDels (c.193_195del in NSUN5, c.1690_1698del in COL9A3) as candidate variants for KC. The verifying results showed that c.341A>T in ERMP1 and c.193_195del in NSUN5 was found in one and two samples, respectively.
Conclusions
Our study suggested that a total of six SNVs in six genes and two InDels in two genes might be considered as candidate variants in Chinese patients with KC.
... The study of molecular genetics of FBN1 contributes to the development of prenatal diagnosis of this gene-related disease, and also contributes to the early diagnosis and risk prediction of high-risk patients. Isolated EL pedigree has been reported many times in different races [7][8][9][10] . Isolated EL may be an independent subtype caused by specific FBN1 mutations or other regulatory factors. ...
... Targeted Next-generation Sequencing Whole blood genomic DNA extraction was performed with DNA extraction kit (Tiangen, Beijing, China) from venous blood. Inheritable genetic vision system-related genes were captured as described [10] . The probands (IV:2 in FAMILY-1, V:2 in FAMILY-2) underwent next-generation sequencing of the gene panel. ...
... According to the reference genome, data were analyzed and provided as described [10] . After variant annotation, we primarily analyzed the nonsynonymous variants, coding indels, splice site variants. ...
Aim:
To summarize the phenotypes and identify the underlying genetic cause of the fibrillin-1 (FBN1) gene responsible for congenital ectopia lentis (EL) in two Chinese families in northern China.
Methods:
A detailed family history and clinical data from all participants were collected by clinical examination. The candidate genes were captured and sequenced by targeted next-generation sequencing, and the results were confirmed by Sanger sequencing. Haplotyping was used to confirm the mutation sequence. Real-time PCR was used to determine the FBN1 messenger ribonucleic acid (mRNA) levels in patients with EL and in unaffected family members.
Results:
The probands and other patients in the two families were affected with congenital isolated EL. A heterozygous FBN1 mutation in exon 21 (c.2420_IVS20-8 delTCTGAAACAinsCGAAAG) was identified in FAMILY-1. A heterozygous FBN1 mutation in exon 14 (c.1633C>T, p.R545C) was identified in FAMILY-2. Each mutation co-segregated with the affected individuals in the family and did not exist in unaffected family members and 200 unrelated normal controls.
Conclusion:
The insertion-deletion mutation (c.2420 IVS20-8delTCTGAAACA insCGAAAG) in the FBN1 gene is first identified in isolated EL. The mutation (c.1633C>T) in the FBN1 gene was a known mutation in EL patient. The variable phenotypes among the patients expand the phenotypic spectrum of EL in a different ethnic background.
Purpose: The purpose of this study was to identify a new candidate gene for keratoconus and congenital cataracts and further investigate its underlying pathogenic mechanisms.
Methods: This study, using a Chinese family with keratoconus and congenital cataracts, 262 patients with sporadic keratoconus, and 20 patients with sporadic congenital cataract as subjects, used clinical and genetic analysis and in vitro cell experiments to detect genetic mutations and further investigate the underlying pathogenic mechanisms.
Results: We found that a novel frameshift mutation of ERCC8 (NM_000082.3: c.394-398del, p. L132Nfs*6) is responsible for familial keratoconus with congenital cataracts. This mutation showed co-segregation with the phenotype in the family. This was revealed in another patient with sporadic keratoconus, absent in the 210 unrelated health controls, and considered to be “disease-causing.” ERCC8 was expressed both in the cornea and lens. Through an in vitro cell experiment, we further demonstrated that the mutant proteins of ERCC8 were degraded and could lead to an insufficient dose of the ERCC8 protein. An insufficient dose reduced the DNA damage repair ability of human corneal fibroblast (HTK) and lens epithelial cells (HLEC) treated with hydrogen peroxide, leading to both cells showing higher DNA damage levels. In addition, it decreased cell viability, resulting in decreased collagen expression in HTK and increased apoptosis in HLEC via aberrant activation of the unfolded protein response. All these results suggested that ERCC8 plays an important role in the normal function of corneal stromal and lens epithelial cells.
Conclusions: Our study showed that ERCC8 is a new gene associated with keratoconus and congenital cataracts.
Introduction
Keratoconus (KC, OMIM: 148300) is a progressive corneal ectatic disorder characterized by thinning and protrusion of cornea resulting in visual decrement.
Materials and Methods
In the current study, we recruited a total of 50 KC patients and 100 case-controls domiciles of Assam, based on preset inclusion and exclusion criteria. All the important and relevant signs and symptoms were recorded. Amsler-Krumeich's (AK) classification was followed to grade KC corneas. We screened for the novel as well as reported sequence variations in five candidate genes namely Lysyl oxidase (LOX), Visual system homeobox 1 (VSX1), MicroRNA 184 (MIR184), Superoxide dismutase 1 (SOD1), and exons 4 and 12 of Transforming growth factor beta-induced (TGFβ-I).
Results
We report a novel double variant p.(Pro32Arg) and p.(Gln67Glu) in the LOX gene in a sporadic male patient with Grade I (OD) and Grade II (OS) of KC. A recurrent variant p.(His244Arg) in the VSX1 gene was also observed in a sporadic female patient with Grade I of KC in both eyes. These variants were absent in 100 unrelated ethnically matched case controls.
Discussion
Ours is the first study on molecular genetic analysis of Keratoconus patients from Assam. The novel variants p.(Pro32Arg) and p.(Gln67Glu) observed further expand the mutational spectrum of the LOX gene associated with KC. We are also the first group to report the recurrent p.(His244Arg) variant in the VSX1 gene from India. The observed variant p.(His244Arg) in the VSX1 gene could be the result of a founder effect and may be investigated further.
Keratoconus is a progressive thinning, steepening and distortion of the cornea which can lead to loss of vision if left untreated. Keratoconus has a complex multifactorial etiology, with genetic and environmental components contributing to the disease pathophysiology. Studies have observed high concordance between monozygotic twins, discordance between dizygotic twins, and high familial segregation indicating the presence of a very strong genetic component in the pathogenesis of keratoconus. The use of genome-wide linkage studies on families and twins, genome-wide association studies (GWAS) on case-controls, next-generation sequencing (NGS)-based genomic screens on both familial and non-familial cohorts have led to the identification of keratoconus candidate genes with much greater success and increased resproducibility of genetic findings. This review focuses on candidate genes identified till date and attempts to understand their role in biological processes underlying keratoconus pathogenesis. In addition, using these genes I propose molecular pathways that could contribute to keratoconus pathogenesis. The pathways identified the presence of direct cross-talk between known candidate genes of keratoconus and remarkably, 28 known candidate genes have a direct relationship among themselves that involves direct protein-protein binding, regulatory activities such as activation and inhibition, chaperone, transcriptional activation/co-activation, and enzyme catalysis. This review attempts to describe these relationships and cross-talks in the context of keratoconus pathogenesis.
This study evaluated whether lithium chloride (LiCl) prevents cytoplasmic accumulation of mutant-transforming growth factor β-induced protein (Mut-TGFBI) in granular corneal dystrophy (GCD) via activation of the autophagy pathway. Levels of TGFBI and microtubule-associated protein 1A/1B-light chain 3 (LC3) in 3 GCD patients and healthy controls were analyzed by immunohistochemistry (IHC) staining and Western blot. Primary corneal fibroblasts were isolated and transfected with wild type or mutant type TGFBI over-expressed vectors, and then treated with LiCl and/or autophagy inhibitor 3-methyladenine (3-MA). Then, levels of TGFBI, glycogen synthase kinase-3 (GSK-3) and LC3-I/-II were detected. Cell viability and transmission electron microscopy assay were also performed. Levels of TGFBI and LC3 were significantly increased in GCD patients. Over-expression of mutant type TGFBI inhibited cell viability and induced autophagy in corneal fibroblasts. LiCl downregulated the expression of TGFBI in mutant type TGFBI over-expressed cells in a dose- and time-dependent manner. LiCl enhanced autophagy in mutant type TGFBI over-expressed cells and recovered cell viability in those cells. However, the effects of LiCl were partly attenuated when autophagy was suppressed by 3-MA. To summarize, treatment with LiCl inhibited the expression of TGFBI and recovery the inhibitory of mutant type TGFBI in cell viability, at least part through enhancing of autophagy. These data strongly suggest that LiCl may be useful in the treatment of GCD.
