Ontology highlight
ABSTRACT:
PROVIDER: PRJNA753967 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15422060_1.fastq.gz | Fastqsanger.gz | |||
| SRR15422060_2.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 2 of 2 |
Similar Datasets
Project description:Matrix Gla protein (MGP) is a vitamin K-dependent post-translationally modified protein, highly expressed in vascular and cartilaginous tissues. It is a potent inhibitor of extracellular matrix mineralization. Biallelic loss of function variants in the MGP gene cause Keutel syndrome, an autosomal recessive disorder characterized by widespread calcification of various cartilaginous tissues and skeletal and vascular anomalies. In this study, we report four individuals from two unrelated families with two heterozygous variants in MGP, both altering the Cysteine 19 residue to phenylalanine or tyrosine. These individuals presented with a spondyloepiphyseal skeletal dysplasia characterized by short stature with a short trunk, diffuse platyspondyly, midface retrusion, progressive epiphyseal anomalies and brachytelephalangism. We investigated the cellular and molecular effects of one of the heterozygous deleterious variants (C19F) using both cell and genetically modified mouse models. Heterozygous ‘knock-in’ mice expressing C19F MGP recapitulated most of the skeletal anomalies observed in the affected individuals. We demonstrated that the main underlying mechanism leading to the observed skeletal dysplasia is endoplasmic reticulum stress-induced apoptosis of the growth plate chondrocytes. Our findings support that heterozygous variants in MGP altering Cys19 residue cause autosomal dominant spondyloepiphyseal dysplasia, a condition distinct from Keutel syndrome both clinically and molecularly.
2024-01-26 | PXD043374 | Pride
Project description:Novel Compound Heterozygous Variants in LTBP2 Associated with Relative Anterior Microphthalmia
| PRJNA846598 | ENA
Project description:Heterozygous OAS1 Gain-of-Function Variants Cause a Polymorphic Autoinflammatory and Immunodeficiency Syndrome
| PRJNA726563 | ENA
Project description:Heterozygous variants in the KAT6A gene encoding the histone lysine acetyltransferase KAT6A (MOZ, MYST3) cause Arboleda-Tham syndrome, an intellectual disability syndrome. The profound effects of pathogenic variants in only one allele of KAT6A on cognitive development and functions raises the question what effects heterozygous and homozygous loss of KAT6A may have on gene expression and chromatin modifications, specifically in a neural cell type that is functionally affected by loss of KAT6A. To address this question, we established that murine neural stem and progenitor cells form fewer neurons after loss of one and two alleles of Kat6a and used these cells to conduct automated chromatin profiling. We determined within the same cell preparation acetylation at histone H3 lysines 9, 14 and 23, RNA polymerase II (POLR2A) and MLL1 occupancy, as well as levels of methylation at histone H3 lysine 4 (H3K4), the MLL1 target, and compared these chromatin profiling results to the effects of loss of KAT6A on gene expression.
2026-04-20 | GSE311724 | GEO
Project description:Heterozygous variants in POLR1A cause diverse human phenotypes
| PRJNA849583 | ENA
Project description:Heterozygous pathogenic variants in POLR1A were identified as the cause of Acrofacial Dysostosis, Cincinnati-type in 2015. Craniofacial anomalies reminiscent of Treacher Collins syndrome were the predominant phenotype observed in the first 3 affected individuals. We have subsequently identified 17 additional individuals with 12 unique (11 novel) heterozygous variants in POLR1A and observed numerous additional phenotypes including developmental delay, infantile spasms, and structural cardiac defects. To understand the pathogenesis of this pleiotropy, we created an allelic series of POLR1A using a combination of in vivo (mouse) and in vitro models. We describe distinct spatiotemporal requirements for Polr1a during mouse embryogenesis and identify a requirement for Polr1a for survival of pre migratory and migratory neural crest cells, forebrain precursors, and the second heart field. We used CRISPR/Cas9 to recapitulate two human alleles in mouse, demonstrating pathogenicity of one and likely benign nature of the other. Our work greatly expands the phenotype of human POLR1A-related disorders, provides new evidence of reduced penetrance and variable expression of POLR1A heterozygous variants, and demonstrates a multi-faceted approach to characterize and define pathogenicity of variants.
2022-08-15 | GSE206197 | GEO
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:Biallelic RNU12 noncoding variants cause CDAGS syndrome
| PRJNA648415 | ENA