Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1243706 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32910701_1.fastq.gz | Fastqsanger.gz | |||
| SRR32910701_2.fastq.gz | Fastqsanger.gz | |||
| SRR32910702_1.fastq.gz | Fastqsanger.gz | |||
| SRR32910702_2.fastq.gz | Fastqsanger.gz | |||
| SRR32910703_1.fastq.gz | Fastqsanger.gz |
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Project description:Squamous cell carcinoma antigen recognized by T cells 3 (SART3) is an RNA binding protein that regulates a diverse array of biological processes, including recycling small nuclear ribonucleic acids (snRNAs) back to the spliceosome. Here we describe nine individuals from six independent families with a multisystem disorder, characterised by intellectual disability, developmental delay, brain anomalies and 46, XY-specific gonadal dysgenesis, who harbour recessive variants in the SART3 gene. Knockdown of the fly orthologue of SART3, Rnp4f, demonstrates a conserved role in neuronal and testicular development. Human induced pluripotent stem cells (iPSCs) carrying patient SART3 variants have disrupted neuronal and gonadal differentiation in vitro. These iPSCs have significant disruption to multiple signalling pathways and complexes, including spliceosome components and mRNA splicing. We propose that biallelic variants in the SART3 gene underlie a novel spliceosomopathy characterised by neuronal defects and testicular dysgenesis.
2023-06-11 | PXD032816 | Pride
Project description:Heterozygous point mutations or genomic deletions of NR0B1 in Xp21.2 result in congenital adrenal hypoplasia and hypogonadotropic hypogonadism, whereas the NR0B1 locus duplications in XY individuals lead to gonadal dysgenesis and a male-to-female dosage-sensitive sex reversal. We previously reported an ~ 257 kb deletion mapping 11 kb upstream to NR0B1 in a XY female with primary amenorrhea, small immature uterus, and gonadal dysgenesis pointing to an alteration of its regulatory region. To identify the potential regulatory elements of NR0B1, we have analyzed its 2 Mb flanking regions using chromosome conformation capture-on-chip (4C) in Sertoli cells and lymphoblasts. We confirm the involvement of the previously proposed regulatory region in the control of NR0B1 expression and describe several novel potential chromatin interactions within the NR0B1 locus that may be involved in sex differentiation.
2014-12-24 | GSE64470 | GEO
Project description:Heterozygous point mutations or genomic deletions of NR0B1 in Xp21.2 result in congenital adrenal hypoplasia and hypogonadotropic hypogonadism, whereas the NR0B1 locus duplications in XY individuals lead to gonadal dysgenesis and a male-to-female dosage-sensitive sex reversal. We previously reported an ~ 257 kb deletion mapping 11 kb upstream to NR0B1 in a XY female with primary amenorrhea, small immature uterus, and gonadal dysgenesis pointing to an alteration of its regulatory region. To identify the potential regulatory elements of NR0B1, we have analyzed its 2 Mb flanking regions using chromosome conformation capture-on-chip (4C) in Sertoli cells and lymphoblasts. We confirm the involvement of the previously proposed regulatory region in the control of NR0B1 expression and describe several novel potential chromatin interactions within the NR0B1 locus that may be involved in sex differentiation. Custom designed 3x720K tiling microarrays covering 4 Mb region (chrX:28,082,100-32,087,100) flanking NR0B1 gene of interest
2014-12-24 | E-GEOD-64470 | biostudies-arrayexpress
Project description:<p>The Gabriella Miller Kids First Pediatric Research Program (Kids First) is a trans-NIH effort initiated in response to the 2014 Gabriella Miller Kids First Research Act and supported by the NIH Common Fund. This program focuses on gene discovery in pediatric cancers and structural birth defects and the development of the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource). Both childhood cancers and structural birth defects are critical and costly conditions associated with substantial morbidity and mortality. Elucidating the underlying genetic etiology of these diseases has the potential to profoundly improve preventative measures, diagnostics, and therapeutic interventions.</p> <p>Whole Genome Sequence (WGS) and phenotypic data from this study are accessible through dbGaP and <a href="https://kidsfirstdrc.org/">kidsfirstdrc.org</a>, where other Kids First datasets can also be accessed. Disorders/Differences of Sex Development (DSD) are congenital conditions in which development of chromosomal, gonadal, or anatomic sex is atypical. DSD are chronic medical conditions collectively affecting ~1% of the population, frequently requiring life-long care by multiple specialists, and carrying a significant public health burden. Some are associated with life-threatening events, such as adrenal crises in Congenital Adrenal Hyperplasia (CAH). DSD are also associated with increased infertility, cancer, gender dysphoria risks, psychosocial distress and pervasive challenges to health-related quality of life (HRQoL) for patients and families. DSD are broadly classified into three categories: sex chromosome DSD, 46,XY DSD and 46,XX DSD, and further classified according to the type of gonad found in the patient (ovary, testis, ovotestis). </p> <p>We were able to increase significantly the diagnostic success for DSD using Whole Exome Sequencing (WES), with the identification of disease-causing and likely pathogenic variants in a third of a cohort of 46,XY patients. We have therefore proposed a shift in the diagnostic approach to DSD to use next-gen sequencing as a first-line clinical test, which could lead to faster and more accurate diagnosis, and orient further clinical management, limiting unnecessary, costly, and often invasive endocrine testing and imaging. However many remain unexplained (over half of the XY cases, a significant minority of XX cases, including most ovotesticular DSD, and most syndromic cases). In addition, the very large phenotypic variability in cases with known variants in the same gene is unexplained. </p> <p>We here propose to use Whole-Genome Sequencing (WGS), which dramatically improves upon exome sequencing, covering both coding and non-coding parts of the genome more uniformly, as an approach to not only improve diagnostic yield, but also to identify novel genes and regulatory elements involved in DSD.</p>
| phs001178 | dbGaP
Project description:This repository contains whole genome long read sequencing data generated using Oxford Nanopore Technologies from a mouse of the Four Core Genotypes cross. By crossing mice with both a deletion of the sex-determining factor Sry on the Y-chromosome and a transgenic insertion of Sry on Chromosome 3, four combinations of gonadal (testis or ovaries) and chromosomal (XX or XY) are generated, namely XYSry-Chr3Sry+ (gonadal and chromosomal males), XYSry- (gonadal females, chromosomal males), XX (gonadal and chromosomal females), XXChr3Sry+ (gonadal males, chromosomal females). The transgenes were on a C57BL6 genetic background which is crossed with a CAST/EiJ female to allow for the distinction of the parental haplotypes. DNA sequencing was done on a liver sample of the XYSry+ genotype.
2024-10-14 | E-MTAB-14291 | biostudies-arrayexpress
Project description:Nuclear receptor subfamily 5 group A member 1 (NR5A1) encodes steroidogenic factor 1 (SF1), a key regulatory factor that determines gonadal development and coordinates endocrine functions. Here, we have established a stem cell-based model of human gonadal development and applied it to evaluate the effects of NR5A1 during the transition from bipotential gonad to testicular cells. We combined directed differentiation of human induced pluripotent stem cells (46,XY) with activation of endogenous NR5A1 expression by conditionally-inducible CRISPR activation. The resulting male gonadal-like cells expressed several Sertoli cell transcripts, secreted anti-Müllerian hormone and responded to follicle-stimulating hormone by producing sex steroid intermediates. These characteristics were not induced without NR5A1 activation. A total of 2691 differentially expressed genetic elements, including both coding and non-coding RNAs, were detected immediately following activation of NR5A1 expression. Of those, we identified novel gonad-related putative NR5A1 targets, such as SCARA5, which we validated also by immunocytochemistry. In addition, NR5A1 activation was associated with dynamic expression of multiple gonad- and infertility-related differentially expressed genes. In conclusion, by combining targeted differentiation and endogenous activation of NR5A1 we have for the first time, been able to examine in detail the effects of NR5A1 in early human gonadal cells. The model and results obtained provide a useful resource for future investigations exploring the causative reasons for gonadal dysgenesis and infertility in humans.
2022-10-25 | GSE186606 | GEO
Project description:This repository contains whole genome sequencing data from mice of the Four Core Genotypes cross. By crossing mice with both a deletion of the sex-determining factor Sry on the Y-chromosome and a transgenic insertion of Sry on Chromosome 3 , four combinations of gonadal (testis or ovaries) and chromosomal (XX or XY) are generated, namely XYSry-Chr3Sry+ (gonadal and chromosomal males), XYSry- (gonadal females, chromosomal males), XX (gonadal and chromosomal females), XXChr3Sry+ (gonadal males, chromosomal females). The transgenes were on a C57BL6 genetic background which is crossed with a CAST/EiJ female to allow for the distinction of the parental haplotypes, or on a pure-bred C57BL6 background. DNA sequencing was done on either liver or ear-punch samples.
2024-10-14 | E-MTAB-13585 | biostudies-arrayexpress
Project description:The ability to transmit genetic information through generations depends on preservation of genome integrity. Genetic abnormalities affect cell differentiation, causing tissue specification defects and cancer. We addressed genomic instability in individuals with Differences of Sex Development (DSD), characterized by gonadal dysgenesis, sex reversal, infertility, high susceptibility for different types of cancer, especially Germ Cell Tumors (GCT), and in men with testicular GCTs. We analyzed the whole proteome of leukocytes and confirmed it with immunoblotting and quantitative PCR analysis. Additional data from tissue biopsies strengthen our observations in peripheral blood. In particular, the analysis of leukocytes and dysgenic gonads uncovered DNA damage phenotypes, supported by changes in DNA damage response mechanisms: altered autophagy and innate immune response, suppressed TP53-dependent DNA repair.
2023-07-20 | PXD033635 | Pride
Project description:Differences of Sex Development (DSD) are a set of conditions where development of chromosomal, gonadal, or anatomical sex is atypical. With overlapping phenotypes and multiple genes involved, poor diagnostic yields are achieved for many of these conditions. The current DSD diagnostic regimen can be augmented by investigating transcriptome/proteome in vivo, but it is hampered by the unavailability of affected gonadal tissue at the relevant developmental stage. We try to mitigate this limitation by reprogramming readily available skin tissue-derived dermal fibroblasts into Sertoli cells (SC), which could then be deployed for different diagnostic strategies. SCs form the target cell type of choice because they act like an organizing center of embryonic gonadal development and many DSD arise when these developmental processes go awry. Methods: We employed a computational predictive algorithm for cell conversions called Mogrify to predict the transcription factors (TFs) required for direct reprogramming of human dermal fibroblasts into SCs. We established trans-differentiation culture conditions where stable transgenic expression of these TFs was achieved in 46, XY adult dermal fibroblasts using lentiviral vectors. The resulting Sertoli like cells (SLCs) were validated for SC phenotype using several approaches. Results: SLCs exhibited Sertoli-like morphological and cellular properties as revealed by morphometry and xCelligence cell behavior assays. They also showed Sertoli-specific expression of molecular markers such as SOX9, PTGDS, BMP4, or DMRT1 as revealed by IF imaging, RNAseq and qPCR. The SLC transcriptome shared about two thirds of its differentially expressed genes with a human adult SC transcriptome and expressed markers typical of embryonic SCs. Notably, SLCs lacked expression of most markers of other gonadal cell types such as Leydig, germ, peritubular myoid or granulosa cells. Conclusions: The trans-differentiation method was applied to a variety of commercially available 46, XY fibroblasts derived from patients with DSD and to a 46, XX cell line. The DSD SLCs displayed altered levels of trans-differentiation in comparison to normal 46, XY-derived SLCs, thus showcasing the robustness of this new trans-differentiation model.
2024-03-01 | GSE246236 | GEO
Project description:This repository contains single-nucleus gene expression profiling from 48 mouse livers of the Four Core Genotypes cross. By crossing mice with both a deletion of the sex-determining factor Sry on the Y-chromosome and a transgenic insertion of Sry on Chromosome 3, four combinations of gonadal (testis or ovaries) and chromosomal (XX or XY) are generated, namely XYSry-Chr3Sry+ (gonadal and chromosomal males), XYSry- (gonadal females, chromosomal males), XX (gonadal and chromosomal females), XXChr3Sry+ (gonadal males, chromosomal females). The transgenes are on a C57BL6 genetic background. From all four genotypes, whole livers were dissected and flash frozen, followed by nuclear extraction and fixation for sci-RNA-seq3.
2024-12-24 | E-MTAB-13987 | biostudies-arrayexpress