A novel splice-site mutation in the LRP5 gene causing Familial Exudative Vitreoretinopathy

Shafienia, Shohreh; Mirzaei, Malihe; Kavosi, Arghavan; Yavarian, Majid

doi:10.1016/j.genrep.2020.100801

Cited by 3 publications

(2 citation statements)

References 37 publications

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“…The LRP5 splice site mutation (NM_002335.4: c.686 + 1 G > T) identified in patients with familial exudative vitreoretinopathy (FEVR) causes LRP5 gene downregulation, resulting in complete retinal detachment and bilateral blindness and decreased BMD (bone mineral density) 144 . Several mutations that interfere with normal LRP5 splicing have been reported in OPPG (osteoporosis–pseudoglioma syndrome) patients, who also present with low BMD 145 .…”

Section: Wnt/β-catenin Pathwaymentioning

confidence: 99%

The implications of alternative pre-mRNA splicing in cell signal transduction

2023

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Cells produce multiple mRNAs through alternative splicing, which ensures proteome diversity. Because most human genes undergo alternative splicing, key components of signal transduction pathways are no exception. Cells regulate various signal transduction pathways, including those associated with cell proliferation, development, differentiation, migration, and apoptosis. Since proteins produced through alternative splicing can exhibit diverse biological functions, splicing regulatory mechanisms affect all signal transduction pathways. Studies have demonstrated that proteins generated by the selective combination of exons encoding important domains can enhance or attenuate signal transduction and can stably and precisely regulate various signal transduction pathways. However, aberrant splicing regulation via genetic mutation or abnormal expression of splicing factors negatively affects signal transduction pathways and is associated with the onset and progression of various diseases, including cancer. In this review, we describe the effects of alternative splicing regulation on major signal transduction pathways and highlight the significance of alternative splicing.

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Section: Wnt/β-catenin Pathwaymentioning

confidence: 99%

The implications of alternative pre-mRNA splicing in cell signal transduction

2023

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“…It is an inherited blinding eye disease with abnormal retinal vascular development. FEVR can be inherited in an autosomal recessive, autosomal dominant, or X‐linked trait (Shafienia et al, 2020 ). In addition to genetic heterogeneity, FEVR also shows a high degree of clinical heterogeneity (Wang et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

A novel frameshift variant in the TSPAN12 gene causes autosomal dominant FEVR

Dai

Xiao

et al. 2022

Molec Gen & Gen Med

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Background Familial exudative vitreoretinopathy (FEVR) is an inherited blinding eye disease with abnormal retinal vascular development. We aim to broaden the variant spectrum of FEVR and provide a basis for molecular diagnosis and genetic consultation. Methods We recruited five FEVR patients from one large Chinese family. Whole‐exome sequencing (WES) and Sanger sequencing were applied to sequence, analyze, and verify variants on genomic DNA samples. Immunocytochemistry, western blot, qPCR, and luciferase assay were performed to test the influence of the variant on the protein expression and activity of the Norrin/β‐catenin pathway. Results We identified a novel heterozygous frameshift variant c.533dupC (p.D179Rfs*6) in Tetraspanin 12 (TSPAN12) gene that is related to FEVR. This variant caused degradation of the entire TSPAN12 protein, which failed to activate Norrin/β‐catenin signaling, possibly causing FEVR. Conclusion Our study revealed a novel frameshift variant D179Rfs*6 in TSPAN12 that is inherited in an autosomal dominant manner. We found that D179Rfs*6 caused a failure to activate Norrin/β‐catenin signaling. This finding broadens the variant spectrum of TSPAN12 and provides invaluable information for the molecular diagnosis of FEVR.

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Early onset high myopia and severe anisometropia associated with familial exudative vitreoretinopathy of irregular dominant inheritance in 12 Chinese families：analysis of refraction features and pathogenic variations

Cheng,

Rong,

et al. 2024

Preprint

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Purpose Familial exudative vitreoretinopathy (FEVR) is a hereditary blinding vitreoretinopathy characterized by anomalous retinal vascularization. In the early stages, patients are mostly asymptomatic and prone to missed diagnosis because the lesion is located in the peripheral part of the retina. Early-onset high myopia and severe anisometropia are often the earliest reasons for ophthalmologic consultation in FEVR patients. However, there are few studies on the genetic variants and clinical phenotypes associated with eoHM-FEVR and anisometropia-FEVR patients. The purpose of this study was to screen the pathogenic variations in 12 FEVR families and analyze the refractive status and pathogenic genes in patients with irregular dominantly inherited FEVR. Methods the patients with clinical diagnoses of eoHM-FEVR or anisometropia-FEVR were evaluated from October 2019 to August 2022. Comprehensive ophthalmic tests were performed on participants to confirm the phenotype. The genotype was identified using whole exon sequencing, and further verified the results among other family members by Sanger sequencing. Normal protein structures were constructed with alphfold, and mutant proteins were visualized and analyzed with pymol software. The pathogenicity of the variants was determined in accordance with the guidelines of the American College of Medical Genetics and Genomics (ACMG). The protein-protein interaction (PPIs) network analysis with STRING and k mean clustering was applied for detecting the interacting of genes in the candidate genes and the ClusPro Server was used for protein-protein docking. Results A total of 12 FEVR families were included in the study, and all the probands were found to have high myopia in both eyes or one eye before the age of 7 years. The pathogenic variants were identified in the genes TSPAN12, LRP5, VCAN, and FZD4 known to be associated with FEVR in 7 probands. FFA examination found that FEVR patients in all families showed the onset of the disease earlier than the previous generation, and the disease gradually worsened. It should be noted that the FEVR probands in all families showed an earlier age of onset than the previous generation and a more severely fundus abnormalities in the fundus examination and fluorescin angiography. Among them, 3 probands had severe anisometropia and asymmetric fundus changes in both eyes and showed the higher the degree of myopia, the worse the best corrected visual acuity and the more serious the degree of FEVR. Cluster analysis show 13 eoHM related gene blong to 3 cluster, which belong to collagen-containing extracellular matrix cellular component, endosome lumen and Wnt signaling pathway respectively. Among the 13 eoHM related genes, FZD4 and LRP2 encode protein can dock by together analyzed by ClusPro software, the same to VCAN and FBN1 encoding protein. The complex protein, FZD4-LRP2 and VCAN-FBN1 play a bridge role among eoHM related gene according to PPI network analysis. Conclusion In this study, the FEVR families showed the phenomenon of irregular dominant inheritance. The asymmetric FEVR manifested as severe anisometropia and the eye with the higher myopia tends to have a more heavily staged FEVR and more pronounced fundus changes. PPIs network analysis revealed important modules of gene interacting and FZD4-LRP2 and VCAN-FBN1 complex protein were potentially related to high myopia development. For patients with high myopia or with obvious anisometropia in both eyes, more attention should be paid clinically to comprehensive examination of the peripheral fundus and early genetic testing.

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A novel splice-site mutation in the LRP5 gene causing Familial Exudative Vitreoretinopathy

Cited by 3 publications

References 37 publications

The implications of alternative pre-mRNA splicing in cell signal transduction

The implications of alternative pre-mRNA splicing in cell signal transduction

A novel frameshift variant in the TSPAN12 gene causes autosomal dominant FEVR

Early onset high myopia and severe anisometropia associated with familial exudative vitreoretinopathy of irregular dominant inheritance in 12 Chinese families：analysis of refraction features and pathogenic variations

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