Ontology highlight
ABSTRACT:
PROVIDER: PRJNA876925 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21424325_1.fastq.gz | Fastqsanger.gz | |||
| SRR21424325_2.fastq.gz | Fastqsanger.gz | |||
| SRR21424326_1.fastq.gz | Fastqsanger.gz | |||
| SRR21424326_2.fastq.gz | Fastqsanger.gz | |||
| SRR21424327_1.fastq.gz | Fastqsanger.gz |
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Project description:Truncating variants in titin can cause dilated cardiomyopathy, however, the role of missense titin variants is less clear. In humans the heterozygous titin A178D variant is associated with dilated cardiomyopathy with left ventricular non-compaction. Using CRISPR-Cas9 mediated homology-directed repair the A178D titin variant was introduced into a mouse model. Homozygous A178D mice showed features of dilated cardiomyopathy. Total RNA was extracted from the left ventricles of WT and homozygous A178D littermate control mice and RNA-sequencing performed. Different patterns of gene expression were identified in wildtype and homozygous A178D left ventricles.
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Project description:Pituitary neuroendocrine tumours (PitNET) are rare neoplasms of the pituitary gland that can overproduce pituitary hormones or cause headaches and visual impairment due to mass effect. Growth hormone overproducing somatotroph PitNETs cause acromegaly leading to wide range of connective tissue, metabolic and oncologic disorders. The medical treamment of acromegaly is somatostin analogues (SSA) in specific cases combined with dopamine agnoists (DA), but almost half of patients excert SSA resistence and potential causes of this is unknown. The aim of this study was to characterize transcriptomic patterns of somatotroph PitNETs specifically assessing impact of SSA treatment effects. We investigated gene expession on several levels and functional models of GH PitNETs - tumour tissue of patients with and without SSA preoperative treamtment, tumour derived pituisphere model and classically used GH3 cell line treated with SSA.
2022-04-08 | GSE200175 | GEO
Project description:Aims: Pathogenic truncating variants in the largest human protein TITIN are a leading cause of dilated cardiomyopathy. Because of the size of the gene encoding TITIN, many missense variations are identified. These are difficult to evaluate in genetic testing, as even individually rare variants are common in aggregate in normal populations. While the majority will be benign, a small subset is pathogenic, but distinction is challenging. Here, we describe the generation of a mouse model to investigate the underlying disease mechanism of a previously reported TITIN A178D missense variant identified in a family with non-compaction and dilated cardiomyopathy. Methods and Results: Heterozygous and homozygous mice carrying the TITIN A178D missense variant were characterised in vivo. Heterozygous mice had no detectable phenotype at any time point observed (up to 1 year). By contrast, homozygous mice developed dilated cardiomyopathy from 3 months. Chronic adrenergic stimulation aggravated the phenotype. Targeted transcript profiling revealed induction of the fetal gene programme and hypertrophic signalling pathways in homozygous mice, and these were confirmed at the protein level. Unsupervised proteomics identified down-regulation of TELETHONIN and FOUR-AND-A-HALF LIM DOMAIN 2, as well as the up-regulation of heat shock proteins and MYELOID LEUKEMIA FACTOR 1. Loss of TELETHONIN from the cardiac Z-disc was accompanied by proteasomal degradation; however, TELETHONIN also accumulated in the cytoplasm. In parallel, a proteo-toxic response was observed in the mice. Conclusions: We have shown that the TITIN A178D missense variant is pathogenic in homozygous mice, resulting in cardiomyopathy. We also provide evidence of the disease mechanism. Because the TITIN A178D variant abolishes binding of TELETHONIN, this leads to its abnormal cytoplasmic accumulation. Subsequent degradation of TELETHONIN by the proteasome results in proteasomal overload, and activation of a proteo-toxic response. The latter appears to be a driving factor for the cardiomyopathy observed in the mouse model.
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Project description:SNP arrays was combined with next generation sequencing (NGS) to identify an LOH in 16q together with an unreported CTCF missense variant in its zinc finger domain. CTCF is within 16q LOH. We found that germline heterozygous variant I446K became homozygous in the tumor due to a loss of heterozygosity rearrangement affecting the whole q arm on chromosome 16. Based on CTCF role in regulating the epigenetic architechture of the genome, our findings reveal CTCF variant I446K as a link between MRD21 and Wilms tumor predisposition.
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Project description:We saw a patient who presented with respiratory distress from birth due to interstitial lung disease. Before the age of three months a diagnosis of nephrotic syndrome was made. Lung biopsy revealed pulmonary interstitial glycogenosis. Despite extensive investigations, no known genetic or infectious cause was found for the congenital nephrotic syndrome. The patient died at the age of 8 months due to respiratory failure. A 20 Mb homozygous region was identified on chromosome 17 in the patient’s DNA, revealing a novel homozygous missense variant in ITGA3 gene.
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Project description:The obesity incidence is increasing worldwide with the urgent need to identify new therapeutics. Obesity is associated with endocrine alterations, arising from changes in the hypothalamic-pituitary hormone axes, leading to reproductive disorders, altered basal metabolism and stress hormone production. The focus of this study was to determine if diet induced obesity alters pituitary gland plasticity, gene expression and hormone production and secretion. Here we performed single cell RNA-sequencing (scRNA-seq) on pituitary glands from control (CTRL) and high fat diet (HFD) fed males and looked at cell type population dynamics and gene expression changes between HFD and CTRL for all hormone-producing cell types. Our study revealed diet-induced changes in pituitary gland plasticity and hormone production that may play a role in altered hormone production in obese patients and consequently, dysregulation of pituitary gland homeostasis.
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Project description:Pathogenic variants in ACTN2, coding for alpha-actinin 2, are known to be rare causes of Hyper-trophic Cardiomyopathy. However, little is known about the underlying disease mechanisms. Adult heterozygous mice carrying the Actn2 M228T variant were phenotyped by echocardiog-raphy. For homozygous mice, viable E15.5 embryonic hearts were analysed by High Resolution Episcopic Microscopy and wholemount staining, complemented by unbiased proteomics, qPCR and Western blotting. Heterozygous Actn2 M228T mice have no overt phenotype. Only mature males show molecular parameters indicative of cardiomyopathy. By contrast, the variant is em-bryonically lethal in the homozygous setting and E15.5 hearts show multiple morphological ab-normalities. Molecular analyses, including unbiased proteomics, identified quantitative abnormal-ities in sarcomeric parameters, cell cycle defects and mitochondrial dysfunction. The mutant al-pha-actinin protein is found to be destabilised, associated with increased activity of the ubiqui-tin-proteosomal system. This missense variant in alpha-actinin renders the protein less stable. In response, the ubiquitin-proteosomal system is activated; a mechanism which has been implicated in cardiomyopathies previously. In parallel, lack of functional alpha-actinin is thought to cause energetic defects through mitochondrial dysfunction. This seems, together with cell cycle defects, the likely cause of death of the embryos. The defects also have wide-ranging morphological con-sequences.
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Project description:Germline mutations in BRAF and other components of the Mitogen-Activated Protein Kinase (MAPK) pathway are associated with the congenital syndromes collectively known as RASopathies. Here, we report the association of Septo-Optic Dysplasia (SOD) including hypopituitarism and Cardio-Facio-Cutaneous (CFC) syndrome in patients harboring mutations in BRAF. Phosphoproteomic analyses demonstrate that these genetic variants are gain-of-function mutations leading to activation of the MAPK pathway. Activation of the MAPK pathway by conditional expression of the BrafV600E/+ allele, or the knock-in BrafQ241R/+ allele (corresponding to the most frequent human CFC-causing mutation, BRAFp.Q257R), leads to abnormal cell lineage determination and terminal differentiation of hormone-producing cells, causing hypopituitarism. Expression of the BrafV600E/+ allele in embryonic pituitary progenitors leads to an increased expression in cell cycle inhibitors, cell growth arrest and apoptosis but not tumour formation. Our findings show a critical role for BRAF in hypothalamo-pituitary-axis development both in mouse and human and implicate mutations found in RASopathies as a cause of endocrine deficiencies in humans
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Project description:Mono- and biallelic variants in the ALDH18A1 gene cause a spectrum of human disorders associated with cutaneous and neurological findings that overlap with both cutis laxa and spastic paraplegia. ALDH18A1 encodes the bifunctional enzyme pyrroline-5-carboxylate synthetase (P5CS) that plays a role in the de novo biosynthesis of proline and ornithine. Here we characterize a previously unreported homozygous ALDH18A1 variant (p.Thr331Pro) in four affected probands from two unrelated families, and demonstrate broad-based alterations in amino acid and antioxidant metabolism. These four patients exhibit variable developmental delay, neurological deficits, and loose skin. Functional characterization of the p.Thr331Pro variant demonstrated a lack of any impact on the steady-state level of the P5CS monomer or mitochondrial localization of the enzyme, but reduced incorporation of the monomer into P5CS oligomers. Using an unlabeled NMR-based metabolomics approach in patient fibroblasts and ALDH18A1-null human embryonic kidney cells expressing the variant P5CS, we identified reduced abundance of glutamate and several metabolites derived from glutamate, including proline and glutathione. Biosynthesis of the polyamine putrescine, derived from ornithine, was also decreased in patient fibroblasts, highlighting the functional consequence on another metabolic pathway involved in antioxidant responses in the cell. RNA sequencing of patient fibroblasts revealed transcript abundance changes in several metabolic and ECM-related genes, adding further insight into pathogenic processes associated with impaired P5CS function. Together these findings shed new light on amino acid and antioxidant pathways associated with ALDH18A1-related disorders, and underscore the value of metabolomic and transcriptomic profiling to discover new pathways that impact disease pathogenesis.
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