Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA846598 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:FOXE3 encodes a highly conserved transcription factor essential for lens development, which is critical for proper eye formation. Biallelic variants in FOXE3 are associated with ocular anomalies, particularly complex microphthalmia (CM), characterized by defects in both the anterior segment and lens. Using next-generation sequencing (NGS) and Sanger sequencing, we identified a heterozygous nonsense variant in compound heterozygosity with a novel single nucleotide variant (SNV) located in a conserved non-coding region 3 kb upstream of FOXE3 in a patient with CM. Genetically engineered mouse lines carrying either the non-coding variant (Foxe3rv) or a frameshift mutation (Foxe3-) in homozygosity (Foxe3rv/rv and Foxe3-/-), along with compound heterozygous (Foxe3rv/Foxe3-) animals, revealed significant differences in the prevalence of ocular anomalies between wild-type controls and mice with homozygous or compound heterozygous mutations, highlighting the detrimental impact of these genetic variants. Furthermore, the progressive decline in FOXE3 protein levels across genotypes underscores its essential role in normal lens development and overall eye structure. These findings illuminate the intricate relationship between genetic variants and their effects on protein functionality and phenotype. In addition, our analysis demonstrated that the non-coding variant impairs USF2 binding, while Usf2 knockdown underscored its essential role in downregulating Foxe3, positioning it as a promising candidate gene in ocular development. These insights emphasize the importance of identifying disease-causing non-coding variants to enhance diagnostic precision for ocular developmental defects and to enrich our understanding of the regulatory mechanisms that govern eye development genes. Finally, this work provides new elements to understand the general mechanisms of ocular growth which, when impaired, leads to microphthalmia.
2025-08-25 | PXD058162 | Pride
Project description:The homeobox-containing transcription factor PAX6 is a key regulator of eye development. Pathogenic heterozygous PAX6 variants lead to variable ocular phenotypes. Missense variants are often associated with milder ocular conditions, although variants in the DNA-binding paired domain which alter target binding lead to severe ocular phenotypes including bilateral microphthalmia, similar to SOX2 anophthalmia syndrome. However, the variant-specific pathway disruption resulting in phenotypic heterogeneity is not well understood.
2025-05-22 | GSE288050 | GEO
Project description:The homeobox-containing transcription factor PAX6 is a key regulator of eye development. Pathogenic heterozygous PAX6 variants lead to variable ocular phenotypes. Missense variants are often associated with milder ocular conditions, although variants in the DNA-binding paired domain which alter target binding lead to severe ocular phenotypes including bilateral microphthalmia, similar to SOX2 anophthalmia syndrome. However, the variant-specific pathway disruption resulting in phenotypic heterogeneity is not well understood.
2025-05-22 | GSE288049 | GEO
Project description:Human fibroblasts from a control or a patient with compound heterozygous variants in KIAA0753 treated with SAG or WNT3A to test responses within canonical Hedgehog or WNT signaling.
2021-08-24 | GSE182286 | GEO
Project description:Hemoglobinopathies are the most common inherited disorders worldwide. Accurate analysis of hemoglobin variants is critical for diagnosis of hemoglobinopathies. Although high-performance liquid chromatography and capillary zone electrophoresis are widely used as screening tools, they possess inherent ambiguities that often preclude accurate detection of hemoglobin variants. Our goal was to develop and optimize a sensitive and specific mass spectrometry-based assay for screening and diagnosis of hemoglobinopathies. A catalog of canonical globin-chain specific peptides as well as mutant peptides corresponding to common hemoglobin variants was generated and their corresponding “heavy” synthetic peptide versions were used as internal standards for quantification and calculation of globin chain ratios. Targeted mass spectrometry analysis was performed by coupling liquid chromatography to a triple quadrupole mass spectrometer, which is the commonest mass spectrometer employed in clinical diagnostics. Dried blood spots from a cohort of 716 individuals (including 211 patients with hemoglobinopathy) were analyzed. The α:β-globin ratios showed a significant difference between normal and β-thalassemia patients, particularly when the disease was homozygous or admixed with structural variants (compound heterozygous). The method presented here permits identification of variants in their homozygous, heterozygous or compound heterozygous states. The intra- and inter-assay precision CV were both <20%. We envision that such mass spectrometry-based assays could be employed as first-line screening assay for hemoglobin variants including sickle cell disease as well as thalassemias.
2025-08-01 | PXD061996 | Pride
Project description:Complex genetic inheritance is thought to underlie many human diseases, yet experimental proof of this model has been elusive. Here, we show that a human congenital heart defect, left ventricular non-compaction (LVNC), can be caused by a combination of rare, inherited heterozygous missense single nucleotide variants. Whole exome sequencing of a nuclear family revealed novel single nucleotide variants of MYH7 and MKL2 in an asymptomatic father while the offspring with severe childhood-onset LVNC harbored an additional missense variant in the cardiac transcription factor, NKX2-5, inherited from an unaffected mother. Mice bred to compound heterozygosity for the orthologous missense variants in Myh7 and Mkl2 had mild cardiac pathology; the additional inheritance of the Nkx2-5 variant yielded a more severe LVNC-like phenotype in triple compound heterozygotes. RNA sequencing identified genes associated with endothelial and myocardial development that were dysregulated in hearts from triple heterozygote mice and human induced pluripotent stem cell–derived cardiomyocytes harboring the three variants, with evidence for NKX2-5’s contribution as a modifier on the molecular level. These studies demonstrate that the deployment of efficient gene editing tools can provide experimental evidence for complex inheritance of human disease.
2019-05-31 | GSE131322 | GEO
Project description:Complex genetic inheritance is thought to underlie many human diseases, yet experimental proof of this model has been elusive. Here, we show that a human congenital heart defect, left ventricular non-compaction (LVNC), can be caused by a combination of rare, inherited heterozygous missense single nucleotide variants. Whole exome sequencing of a nuclear family revealed novel single nucleotide variants of MYH7 and MKL2 in an asymptomatic father while the offspring with severe childhood-onset LVNC harbored an additional missense variant in the cardiac transcription factor, NKX2-5, inherited from an unaffected mother. Mice bred to compound heterozygosity for the orthologous missense variants in Myh7 and Mkl2 had mild cardiac pathology; the additional inheritance of the Nkx2-5 variant yielded a more severe LVNC-like phenotype in triple compound heterozygotes. RNA sequencing identified genes associated with endothelial and myocardial development that were dysregulated in hearts from triple heterozygote mice and human induced pluripotent stem cell–derived cardiomyocytes harboring the three variants, with evidence for NKX2-5’s contribution as a modifier on the molecular level. These studies demonstrate that the deployment of efficient gene editing tools can provide experimental evidence for complex inheritance of human disease.
2019-05-31 | GSE111394 | GEO
Project description:Purpose: Our single-cell RNAseq data show that LTBP2 is a marker of a cancer associated fibroblast subpopulation in colorectal cancer liver metastases. Moreover, MTT assays of cultured fibroblasts treated with anti-LTBP2 antibodies suggest that LTBP2 is essential for their survival. The goal of this study is to understand the role of LTBP2 in fibroblasts. Methods: Normal olon fibroblasts (CCD18Co) were transfected 48h with siRNA containing an anti-LTBP2 or a non target sequence. Cell monolayer total RNA of 3 biological replicates was then extracted and submitted to Illumina RNAseq using NovaSeq6000. Results: Transcriptomics revealed massive changes in gene expression when LTBP2 is knocked down: 496 genes were differentially expressed between the colon fibroblasts treated with siRNA anti-LTBP2 and NT. Those genes are implicated in diverse biological processes such as extracellular matrix organization, angiogenesis or cell adhesion. Conclusions: Our study explored LTBP2 functions in normal fibroblasts. RNAseq data support its important role. After 48h, LTBP2 silencing induces changes in gene expression of numerous genes involved in fibroblast functions.
2022-11-22 | GSE191323 | GEO