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PROVIDER: PRJNA752456 | ENA |
REPOSITORIES: ENA
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Project description:Blood-retina barrier (BRB) formation and retinal angiogenesis depend on beta-catenin signaling induced by the ligand norrin (NDP), the receptor frizzled4 (FZD4), co-receptor LRP5, and the tetraspanin TSPAN12. Impaired NDP/FZD4 signaling causes familial exudative vitreoretinopathy (FEVR), which may lead to blindness. Endothelial-cell specific inactivation of the Tspan12 gene at P28 using a Cdh5-CreERT2 driver shows that TSPAN12 functions in ECs to promote vascular morphogenesis and BRB formation in developing mice, and BRB maintenance in adult mice. 12 month after Tspan12 inactivation and loss of BRB maintenance with massive IgG and albumin extravasation we observe complement activation, cystoid edema, and impaired beta-wave in electroretinograms. RNA-Seq 6 month after Tspan12 inactivation provides a detailed view on the transcriptional response, including activation of antibody effector systems (complement and Fc receptors), inflammation and microglia responses, extracellular matrix organization and remodeling, and other responses.
2018-10-29 | GSE113878 | GEO
Project description:bEnd.3 cells were treated with NDP (Norrin) or F4L5.13 (FZD4-LRP5 agonist) for 8 or 24 hours
2021-05-03 | GSE166764 | GEO
Project description:Background: Causative genes are mostly unknown for the mismatch repair-proficient category of familial colorectal cancers designated as FCCTX. Recent evidence suggests shared susceptibility factors between colorectal and hematological malignancies. Study design: We investigated 28 FCCTX families by exome sequencing, supplemented with whole genome sequencing, RNA-sequencing, and tumor studies to identify the predisposing genes. Guided by the findings, germline and somatic exomes of ~400 patients with acute leukemia, myelodysplastic syndrome, and myeloma were subsequently examined. Results: A family with hematological and solid malignancies revealed a truncating variant in the DEAH-box RNA helicase gene DHX40 co-segregating with disease in seven family members. Neoplastic tissues revealed no apparent “second hit”, implying a haploinsufficiency model of tumorigenesis. DHX40 siRNA-treated cell lines exhibited a 13% increase in aberrantly spliced transcripts vs. GAPDH-siRNA or non-target siRNA-treated cells. Two additional families showed truncating germline variants in the TDRD9 and TDRD5 genes encoding Tudor domain-containing RNA-binding proteins. In the hospital-based hematological series, 18% of germline and 28% of somatic exomes revealed possibly pathogenic DEAD/H box gene variants, including somatic variants of DHX40 in four. Conclusions: This study identifies DHX40, TDRD9, and TDRD5 as novel candidate genes for FCCTX predisposition. In the family segregating the truncating DHX40 variant, two carriers had hematological neoplasia, suggesting possible analogy to DDX41, a DEAD-box RNA helicase gene previously linked to myeloid malignancies. Our findings emphasize aberrant RNA metabolism behind FCCTX and hematological neoplasia.
2023-11-08 | GSE228991 | GEO
Project description:To know genomic alterations of the respective situation of the revised Bethesda criteria, we investigated the impact of somatic variants and gene expression using colorectal tumor tissues. Using Exome-seq and RNAseq analysis, we identified novel somatic variants that are significantly associated with Bethesda criteria. Using the markers, we predicted the the therapeutic target of familial colorectal cancer. This series includes only the RNA-seq data.
2020-11-04 | GSE132024 | GEO
Project description:CDAGS Syndrome is a rare congenital disorder characterized by Craniosynostosis, Delayed closure of the fontanelles, cranial defects, clavicular hypoplasia, Anal and Genitourinary malformations, and Skin manifestations. We performed exome sequencing to identify the underlying molecular cause in five patients with CDAGS syndrome from four distinct families. Whole exome sequencing revealed rare variants that disrupt highly conserved nucleotides within the RNU12 gene. RNU12 encodes a small nuclear RNA that is a component of the minor spliceosome and is essential for minor intron splicing. Targeted sequencing confirmed allele segregation within the four families. All five patients in this cohort have a rare variant on one allele that either disrupts the secondary structure or the Sm binding site of the RNU12 snRNA. The variant on the other allele, shared among all five cases, alters a highly conserved nucleotide within the precursor U12 snRNA 3’ extension that is absent in 1440 unrelated healthy controls. All of the variants are either rare or absent from all searched public databases. Whole transcriptome sequencing analysis identified gene dysregulation and specific defects in intron retention in a subset of minor intron splicing. These findings provide evidence of the involvement of RNU12 in craniosynostosis, anal and genitourinary patterning and cutaneous disease.
2021-07-23 | GSE155099 | GEO
Project description:Here, N-myristolyation, one kind post-translational modification, and its enzyme NMT1 but not NMT2, were found to be critical in liver cancer. Two categories of proteins, i.e. N-myristolyation down-regulated (NDP) and up-regulated protein (NUP) were revealed negatively and positively regulated by NMT1, respectively. Both NDP and NUP could be N-myristolyated by NMT1 indispensible of POTEE. However, N-myristolyation decreased and increased stability of NDP and NUP, respectively. NDP-specific binding protein RPL7A facilitated HISTIH4H, which has ubiquitin E3 ligase function, to ubiquitinate NDP. By contrast, NUP-specific binding protein HBB prevented NUP from ubiquitination by HISTIH4H. Notably, function of RPL7A and HBB were all NMT1-dependent. Moreover, NDP suppressed while NUP stimulated transformative phenotypes. Clinically, higher levels of NMT1 and NUP with lower levels of NDP had worse prognostic outcome. Collectively, N-myristolyation by NMT1 suppresses anti-tumorigenic NDP, whereas stimulates pro-tumorigenic NUP by interfering their ubiquitination to finally result in a pro-tumorigenic outcome in liver cancer.
2021-09-08 | PXD011764 | Pride
Project description:Pathogenic variants in multiple X-linked genes have been implicated in syndromic and non- syndromic intellectual disability disorders. The gene ZFX on Xp22.11 encodes a transcription factor that has been linked to diverse processes including oncogenesis and development, but germline variants have not previously been reported in association with disease. Here, we present clinical and molecular characterization of 18 patients with germline ZFX variants. Exome or genome sequencing revealed 11 variants in 18 subjects (14 males and 4 females) from 16 unrelated families. Four missense variants were identified in 11 subjects, with seven frameshift variants in the remaining individuals. Clinical findings included developmental delay/intellectual disability, behavioral abnormalities, hypotonia, and congenital anomalies. Overlapping and recurrent facial features were identified in all subjects, including thickening and medial broadening of eyebrows, variations in the shape of the face, external eye abnormalities, smooth and/or long philtrum and ear abnormalities. Hyperparathyroidism was found in 4 families with missense variants and enrichment of different types of tumors was also observed. In molecular studies, variants in the DNA-binding domain demonstrated differential expression of target genes relative to wild-type ZFX in cultured cells, suggesting a gain or loss of transcriptional activity. Additionally, a zebrafish model of ZFX loss displayed an altered behavioral phenotype, supporting the pathogenicity of predicted loss- of-function frameshift variants. Our clinical and experimental data support that variants in ZFX cause a novel X-linked intellectual disability syndrome characterized by a recurrent facial gestalt, neurocognitive and behavioral abnormalities, and an increased risk for congenital anomalies and hyperparathyroidism.
2023-11-30 | GSE218689 | GEO
Project description:Pathogenic variants in multiple X-linked genes have been implicated in syndromic and non- syndromic intellectual disability disorders. The gene ZFX on Xp22.11 encodes a transcription factor that has been linked to diverse processes including oncogenesis and development, but germline variants have not previously been reported in association with disease. Here, we present clinical and molecular characterization of 18 patients with germline ZFX variants. Exome or genome sequencing revealed 11 variants in 18 subjects (14 males and 4 females) from 16 unrelated families. Four missense variants were identified in 11 subjects, with seven frameshift variants in the remaining individuals. Clinical findings included developmental delay/intellectual disability, behavioral abnormalities, hypotonia, and congenital anomalies. Overlapping and recurrent facial features were identified in all subjects, including thickening and medial broadening of eyebrows, variations in the shape of the face, external eye abnormalities, smooth and/or long philtrum and ear abnormalities. Hyperparathyroidism was found in 4 families with missense variants and enrichment of different types of tumors was also observed. In molecular studies, variants in the DNA-binding domain demonstrated differential expression of target genes relative to wild-type ZFX in cultured cells, suggesting a gain or loss of transcriptional activity. Additionally, a zebrafish model of ZFX loss displayed an altered behavioral phenotype, supporting the pathogenicity of predicted loss- of-function frameshift variants. Our clinical and experimental data support that variants in ZFX cause a novel X-linked intellectual disability syndrome characterized by a recurrent facial gestalt, neurocognitive and behavioral abnormalities, and an increased risk for congenital anomalies and hyperparathyroidism.
2023-11-30 | GSE218688 | GEO
Project description:Psoriasis is a common inflammatory disorder of the skin and other organs. We have determined that mutations in CARD14, encoding an NF-kB activator within skin epidermis, account for PSORS2. Here we describe fifteen additional rare, missense variants in CARD14, their distribution in seven psoriasis cohorts (>6,000 cases and >4,000 controls), and their effects on NF-kB activation and the transcriptome of keratinocytes. There was an excess of rare variants within CARD14 in cases versus controls (burden test p-value = 0.0015). Some variants were only seen in a single case and included putative pathogenic mutations (c.424G>A [p.Glu142Lys], c.425A>G [p.Glu142Gly]) and the generalized pustular psoriasis mutation, c.413A>C (p.Glu138Ala), that lie within the coiled-coil domain of CARD14. The c.349G>A (p.Gly117Ser) familial psoriasis mutation was present at a frequency of 0.0005 in cases of European ancestry. CARD14 variants led to a range of NF-kB activities, with putative pathogenic variants leading to levels >2.5-fold higher than wildtype CARD14. Two variants (c.511C>A [p.His171Asn] and c.536G>A [p.Arg179His]) required stimulation with TNF-a to achieve significant increases in NF-kB levels. Transcriptome profiling of wildtype and variant CARD14 transfectants in keratinocytes differentiated likely pathogenic mutations from neutral variants such as polymorphisms. Over 20 CARD14 polymorphisms were also genotyped and meta-analysis revealed association of psoriasis with rs11652075 (c.2458C>T/p.Arg820Trp; p-value = 2.1x10-6). In the two largest psoriasis cohorts, evidence for association increased when rs11652075 was conditioned on HLA-Cw*0602 (PSORS1). These studies contribute to our understanding of the genetic basis of psoriasis and illustrate the challenges faced in identifying pathogenic variants in common disease. Keratinocytes were transfected with wildtype Cardsh or one of 16 Card14 mutations (17 total samples). The cells were collected and RNA extracted to determine the effect of these mutations compared to wildtype Card14. No replicates are included.
2012-05-08 | E-GEOD-36381 | biostudies-arrayexpress