Dysgenesis and dysfunction of pancreas and pituitary due to FOXA2 gene defects

2021 ◽  
Author(s):  
Sare Betul Kaygusuz ◽  
Esra Arslan Ates ◽  
Maria Lillina Vignola ◽  
Burcu Volkan ◽  
Bilgen Bilge Geckinli ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Developmental Disorders ◽  
De Novo ◽  
Luciferase Reporter ◽  
Forkhead Box ◽  
First Case ◽  
The Central Nervous System ◽  
Gene Defects ◽  
Congenital Hypopituitarism ◽  
Pancreatic Hypoplasia

Abstract Context Developmental disorders of the pituitary gland leading to congenital hypopituitarism can either be isolated or associated with extra-pituitary abnormalities (syndromic hypopituitarism). A large number of syndromic hypopituitarism cases are linked to mutations in transcription factors. The Forkhead box A2 (FOXA2) is a transcription factor that plays a key role in the central nervous system, foregut and pancreatic development. Objective To characterize two patients with syndromic hypopituitarism due to FOXA2 gene defects. Results We report a novel heterozygous nonsense c.616C>T (p.Q206X) variant, which leads to a truncated protein that lacks part of the DNA-binding domain of FOXA2, resulting in impaired transcriptional activation of the GLUT2-luciferase reporter. The patient is the sixth patient described in the literature with a FOXA2 mutation, and the first patient exhibiting pancreatic hypoplasia. We also report a second patient with a novel de novo 8.53 megabase (Mb) deletion of 20p11.2 that encompasses FOXA2, who developed diabetes mellitus that responded to sulfonylurea treatment. Conclusions Our two cases broaden the molecular and clinical spectrum of FOXA2-related disease, reporting the first nonsense mutation and the first case of pancreatic dysgenesis.

Gliosarcomas with the BRAF V600E mutation: a report of two cases and review of the literature

2017 ◽  
Vol 70 (12) ◽  
pp. 1079-1083 ◽  
Author(s):  
Leiming Wang ◽  
Jian Sun ◽  
Zhuo Li ◽  
Li Chen ◽  
Yongjuan Fu ◽  
...  
Keyword(s):  
De Novo ◽  
Malignant Neoplasm ◽  
Genetic Alterations ◽  
Braf V600e Mutation ◽  
The Other ◽  
Braf V600e ◽  
Review Of The Literature ◽  
Sarcomatous Component ◽  
First Case ◽  
The Central Nervous System

Gliosarcoma, which is regarded as a variant of glioblastoma, is a rare malignant neoplasm of the central nervous system. Both its sarcomatous component and glial component are reported to share significant clinical and genetic similarities. However, gliosarcomas are considered to be characterised by a lack of the BRAF V600E mutation. Here, we report two cases of gliosarcoma harbouring the BRAF V600E mutation, of which one case appears to have arisen de novo, while the other likely arose from ganglioglioma. Interestingly, the BRAF V600E mutation was detected only in the glial component in the first case, but was present in both the glial and the sarcomatous components in the recurrent gliosarcoma. Furthermore, the different mutation state of BRAF V600E in our two cases suggests that the malignant transformation of gliosarcoma might have different underlying genetic alterations and mechanisms in de novo versus recurrent gliosarcoma.

scholarly journals Cell wall integrity signaling regulates cell wall regeneration via transcriptional activation in Chlamydomonas reinhardtii

2019 ◽  
Author(s):  
Evan Cronmiller ◽  
Deepak Toor ◽  
Nai Chun Shao ◽  
Thamali Kariyawasam ◽  
Ming Hsiu Wang ◽  
...  
Keyword(s):  
Cell Wall ◽  
Transcriptional Activation ◽  
Cell Walls ◽  
De Novo ◽  
Intact Cell ◽  
Gene Activation ◽  
Cell Wall Integrity ◽  
Luciferase Reporter ◽  
Mrna Accumulation ◽  
Signaling Mechanisms

AbstractAn intact cell wall is critical for protecting the cell from osmotic challenges and harmful environments. Signaling mechanisms are necessary to monitor cell wall integrity and to regulate cell wall production and remodeling during growth and division cycles. The green alga, Chlamydomonas, has a proteinaceous cell wall of defined structure that is readily removed by gametolysin (g-lysin), a metalloprotease released during sexual mating. Naked cells treated with g-lysin induce the mRNA accumulation of > 100 cell wall-related genes within an hour, offering a system to study signaling and regulatory mechanisms for de novo cell wall assembly. Combining quantitative RT-PCR and luciferase reporter assays to probe transcript accumulation and promoter activity, we revealed that up to 500-fold upregulation of cell wall-related genes was driven at least partly by transcriptional activation upon g-lysin treatment. To investigate how naked cells trigger this rapid transcriptional activation, we tested whether osmotic stress and cell wall integrity are involved in this process. Under a constant hypotonic condition, comparable levels of cell wall-gene activation were observed by g-lysin treatment. In contrast, cells in an iso- or hypertonic condition showed up to 80% reduction in the g-lysin-induced gene activation, suggesting that hypotonic conditions are required for full-scale responses to g-lysin treatment. To test whether mechanical perturbation is involved, we isolated and examined a new set of cell wall mutants with defective or little cell walls. All cell wall mutants examined showed a constitutive upregulation of cell wall-related genes at the level, which would only be achieved by the g-lysin treatment in wild-type cells. Our study suggests a signaling that monitors mechanical defects of cell walls and regulates cell wall-gene expression in Chlamydomonas, which may relate to cell wall integrity signaling mechanisms in plants.

scholarly journals Endovascular repair of de novo post-stenotic aortic coarctation aneurysms with complex collateral supply: two cases with long and medium term follow-up

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Omar Abdel-Hadi ◽  
John Thomson ◽  
Simon J. McPherson
Keyword(s):  
Stent Graft ◽  
Endovascular Repair ◽  
Aortic Coarctation ◽  
De Novo ◽  
Aortic Aneurysms ◽  
Medium Term ◽  
First Case ◽  
Case Presentations ◽  
Selective Embolisation

Abstract Purpose To report the technical details and outcomes of the endovascular repair of two cases of de novo post-stenotic aortic coarctation aneurysms complicated by complex collateral supply. Case presentations Two patients with thoracic aortic aneurysms complicated by complex aneurysm sac collaterals distal to a previously untreated thoracic aortic coarctation have been treated at our institution. Open surgical intervention was deemed to carry a high risk of haemorrhage due to the degree and complexity of arterial collateralisation. In the first case, selective embolisation of collateral vasculature was performed prior to successful exclusion of the aneurysm with a thoracic endovascular stent-graft and then balloon-expandable stent dilatation of the coarctation stenosis. In the second case, the additional technique of using a jailed sheath within the aneurysm sac allowed for selective embolisation of previously inconspicuous collaterals after deployment of the stent-graft and stent combination. Results Technical success was achieved in both patients with successful occlusion of the aneurysm, with no recorded complications or aneurysm sac perfusion in the long and medium term follow up periods respectively. Conclusion De novo post stenotic aortic coarctation aneurysms are rare. Endovascular repair is a safe and durable technique that provides a less invasive alternative to open surgical repair. The use of a jailed sheath allows for complete selective embolisation of complex collaterals avoiding a type II aneurysm endoleak.

scholarly journals Pustular Rash in Crohn’s Patient on Ustekinumab Raises Concern for Drug-Induced Paradoxical Psoriasis

2021 ◽  
pp. 662-666
Author(s):  
Mitra Barahimi ◽  
Scott Lee ◽  
Kindra Clark-Snustad
Keyword(s):  
Side Effect ◽  
De Novo ◽  
Pustular Psoriasis ◽  
Initial Weight ◽  
Drug Induced ◽  
Clinical Recurrence ◽  
Potential Side Effect ◽  
First Case ◽  
Tnf Antagonist ◽  
Subcorneal Pustular Dermatosis

We report the case of a 51-year-old male with Crohn’s disease (CD) who developed a reproducible pustular rash after ustekinumab (UST) administration. The patient first presented with a pustular rash on his hands, body, extremities, and scalp starting 5 weeks after his initial weight-based UST induction. The rash resolved spontaneously, then recurred 4 weeks after his first subcutaneous maintenance dose of UST 90 mg. Biopsy of the affected area demonstrated subcorneal pustular dermatosis (SPD). UST was discontinued and the rash resolved. Unfortunately, the patient experienced clinical recurrence of CD, and given prior failure of multiple CD medications, UST was restarted with premedication. Two weeks after UST re-induction, the rash recurred, though less severe. Given improvement in CD symptoms, UST was continued and the rash managed with topical corticosteroids. This is the first case of drug-induced SPD associated with UST. One case report has previously described de novo pustular psoriasis associated with UST in a patient with CD and enteropathic arthritis. Notably, SPD and pustular psoriasis can be histologically indistinguishable. The development of a paradoxical psoriasiform rash is thought to be one of the few dose and duration dependent side effects of TNF-antagonist therapy but has not previously been established as a side effect of UST. This case demonstrates a new potential side effect of UST.

scholarly journals MED12-Related (Neuro)Developmental Disorders: A Question of Causality

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 663
Author(s):  
Stijn van de Plassche ◽  
Arjan PM de Brouwer
Keyword(s):  
Developmental Disorders ◽  
De Novo ◽  
Expression Patterns ◽  
Mediator Complex ◽  
Gene Expression Patterns ◽  
Facial Dysmorphism ◽  
Regulation Of Transcription ◽  
Feeding Difficulties ◽  
Missense Variants ◽  
Pathogenic Variants

MED12 is a member of the Mediator complex that is involved in the regulation of transcription. Missense variants in MED12 cause FG syndrome, Lujan-Fryns syndrome, and Ohdo syndrome, as well as non-syndromic intellectual disability (ID) in hemizygous males. Recently, female patients with de novo missense variants and de novo protein truncating variants in MED12 were described, resulting in a clinical spectrum centered around ID and Hardikar syndrome without ID. The missense variants are found throughout MED12, whether they are inherited in hemizygous males or de novo in females. They can result in syndromic or nonsyndromic ID. The de novo nonsense variants resulting in Hardikar syndrome that is characterized by facial clefting, pigmentary retinopathy, biliary anomalies, and intestinal malrotation, are found more N-terminally, whereas the more C-terminally positioned variants are de novo protein truncating variants that cause a severe, syndromic phenotype consisting of ID, facial dysmorphism, short stature, skeletal abnormalities, feeding difficulties, and variable other abnormalities. This broad range of distinct phenotypes calls for a method to distinguish between pathogenic and non-pathogenic variants in MED12. We propose an isogenic iNeuron model to establish the unique gene expression patterns that are associated with the specific MED12 variants. The discovery of these patterns would help in future diagnostics and determine the causality of the MED12 variants.

scholarly journals Genome-Wide Identification and Analysis of the APETALA2 (AP2) Transcription Factor in Dendrobium officinale

2021 ◽  
Vol 22 (10) ◽  
pp. 5221
Author(s):  
Danqi Zeng ◽  
Jaime A. Teixeira da Silva ◽  
Mingze Zhang ◽  
Zhenming Yu ◽  
Can Si ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Flower Development ◽  
Regulatory Elements ◽  
Negative Control ◽  
Dendrobium Officinale ◽  
Luciferase Reporter ◽  
Pcr Analysis ◽  
Luciferase Reporter Gene ◽  
Genome Wide ◽  
Ap2 Transcription Factor

The APETALA2 (AP2) transcription factors (TFs) play crucial roles in regulating development in plants. However, a comprehensive analysis of the AP2 family members in a valuable Chinese herbal orchid, Dendrobium officinale, or in other orchids, is limited. In this study, the 14 DoAP2 TFs that were identified from the D. officinale genome and named DoAP2-1 to DoAP2-14 were divided into three clades: euAP2, euANT, and basalANT. The promoters of all DoAP2 genes contained cis-regulatory elements related to plant development and also responsive to plant hormones and stress. qRT-PCR analysis showed the abundant expression of DoAP2-2, DoAP2-5, DoAP2-7, DoAP2-8 and DoAP2-12 genes in protocorm-like bodies (PLBs), while DoAP2-3, DoAP2-4, DoAP2-6, DoAP2-9, DoAP2-10 and DoAP2-11 expression was strong in plantlets. In addition, the expression of some DoAP2 genes was down-regulated during flower development. These results suggest that DoAP2 genes may play roles in plant regeneration and flower development in D. officinale. Four DoAP2 genes (DoAP2-1 from euAP2, DoAP2-2 from euANT, and DoAP2-6 and DoAP2-11 from basal ANT) were selected for further analyses. The transcriptional activation of DoAP2-1, DoAP2-2, DoAP2-6 and DoAP2-11 proteins, which were localized in the nucleus of Arabidopsis thaliana mesophyll protoplasts, was further analyzed by a dual-luciferase reporter gene system in Nicotiana benthamiana leaves. Our data showed that pBD-DoAP2-1, pBD-DoAP2-2, pBD-DoAP2-6 and pBD-DoAP2-11 significantly repressed the expression of the LUC reporter compared with the negative control (pBD), suggesting that these DoAP2 proteins may act as transcriptional repressors in the nucleus of plant cells. Our findings on AP2 genes in D. officinale shed light on the function of AP2 genes in this orchid and other plant species.

scholarly journals C-Terminal Region of STAT-1α Is Not Necessary for Its Ubiquitination and Degradation Caused by Mumps Virus V Protein

2002 ◽  
Vol 76 (24) ◽  
pp. 12683-12690 ◽  
Author(s):  
Noriko Yokosawa ◽  
Shin-ichi Yokota ◽  
Toru Kubota ◽  
Nobuhiro Fujii
Keyword(s):  
Amino Acid ◽  
Transcriptional Activation ◽  
Tandem Repeats ◽  
Mumps Virus ◽  
Terminal Region ◽  
Single Amino Acid ◽  
Luciferase Reporter ◽  
Enhancer Element ◽  
V Protein ◽  
Gene Assay

ABSTRACT Constitutive levels of production of STAT-1 were reduced by 10 h postinfection (p.i.) and significantly lost by 24 h p.i. in FL cells acutely infected with mumps virus (MuV). This result was consistent with that observed in previous studies and experiments with cells persistently infected with MuV (FLMT cells). There was a marked decrease in the amount of STAT-1 in cells expressing MuV accessory protein V (MuV-V). Furthermore, single amino acid substitutions in the Cys-rich region of V protein (Vc189a, Vc207a, and Vc214a) showed that each cysteine residue plays an important role in the decrease in STAT-1 production, but substitution of a histidine residue at amino acid position 203 had no effect. These events and the resultant suppression of the alpha interferon (IFN-α) response were confirmed by a luciferase reporter gene assay with five tandem repeats of the IFN-α-stimulated response element as an enhancer element of the firely luciferase gene. STAT-1 production was restored and detectable in FLMT cells treated with a proteosome inhibitor, such as MG132 or lactacystin. In the presence of MG132, ubiquitination of STAT-1 and the interaction of MuV-V with STAT-1 were demonstrated in FLMT cells by immunoprecipitation with anti-STAT-1 antibody. The same results for the interaction and ubiquitination were obtained in experiments with an expression vector for a C-terminal deletion mutant of STAT-1. The truncated STAT-1 molecules were degraded in the presence of MuV-V. Therefore, the C-terminal region (transcriptional activation and Src homology 2 domains) of STAT-1 is not necessary for its degradation caused by MuV-V. Our data suggest that MuV-V promotes ubiquitination and degradation of STAT-1.

scholarly journals p53 upregulated by HIF-1α promotes hypoxia-induced G2/M arrest and renal fibrosis in vitro and in vivo

2018 ◽  
Vol 11 (5) ◽  
pp. 371-382 ◽  
Author(s):  
Limin Liu ◽  
Peng Zhang ◽  
Ming Bai ◽  
Lijie He ◽  
Lei Zhang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcriptional Activation ◽  
Renal Fibrosis ◽  
Intraperitoneal Administration ◽  
Luciferase Reporter ◽  
Loss Of Function ◽  
P53 Expression ◽  
Tubular Cells

Abstract Hypoxia plays an important role in the genesis and progression of renal fibrosis. The underlying mechanisms, however, have not been sufficiently elucidated. We examined the role of p53 in hypoxia-induced renal fibrosis in cell culture (human and rat renal tubular epithelial cells) and a mouse unilateral ureteral obstruction (UUO) model. Cell cycle of tubular cells was determined by flow cytometry, and the expression of profibrogenic factors was determined by RT-PCR, immunohistochemistry, and western blotting. Chromatin immunoprecipitation and luciferase reporter experiments were performed to explore the effect of HIF-1α on p53 expression. We showed that, in hypoxic tubular cells, p53 upregulation suppressed the expression of CDK1 and cyclins B1 and D1, leading to cell cycle (G2/M) arrest (or delay) and higher expression of TGF-β, CTGF, collagens, and fibronectin. p53 suppression by siRNA or by a specific p53 inhibitor (PIF-α) triggered opposite effects preventing the G2/M arrest and profibrotic changes. In vivo experiments in the UUO model revealed similar antifibrotic results following intraperitoneal administration of PIF-α (2.2 mg/kg). Using gain-of-function, loss-of-function, and luciferase assays, we further identified an HRE3 region on the p53 promoter as the HIF-1α-binding site. The HIF-1α–HRE3 binding resulted in a sharp transcriptional activation of p53. Collectively, we show the presence of a hypoxia-activated, p53-responsive profibrogenic pathway in the kidney. During hypoxia, p53 upregulation induced by HIF-1α suppresses cell cycle progression, leading to the accumulation of G2/M cells, and activates profibrotic TGF-β and CTGF-mediated signaling pathways, causing extracellular matrix production and renal fibrosis.

scholarly journals The rare hemoglobin variant Hb Mizuho: report of a Swiss family and literature review

2021 ◽  
Author(s):  
Linet Njue ◽  
Cesare Medri ◽  
Peter Keller ◽  
Miriam Diepold ◽  
Behrouz Mansouri Taleghani ◽  
...  
Keyword(s):  
Literature Review ◽  
Hemolytic Anemia ◽  
De Novo ◽  
Clinical History ◽  
Molecular Techniques ◽  
De Novo Mutation ◽  
First Case ◽  
History Of ◽  
Transfusion Dependency ◽  
Unstable Hemoglobin

AbstractHb Mizuho is a very rare unstable hemoglobin; here, we describe the clinical history of three Swiss family members with Hb Mizuho together with a systematic review of the previously six published cases. The clinical history of the adult woman we report here is unique since this is the first Hb Mizuho presenting with Moyamoya complications and the first case reported with long-term erythrocyte exchange. The literature review showed that Hb Mizuho was mainly reported as a de novo mutation, with the exception of children descended from known cases. All published patients with this unstable hemoglobin showed severe hemolytic anemia with the exception of one; all were regularly transfused. Patients with higher HbF levels might require fewer transfusions. All patients underwent splenectomy at a median age of 4 years and had variable clinical improvement; some achieved complete resolution of transfusion dependency after splenectomy. Iron overload in Hb Mizuho patients seems to be mainly attributed to transfusions and has less to do with ineffective erythropoiesis. Diagnosis might be challenging; a normal hemoglobin electrophoresis should not rule out the diagnosis of unstable hemoglobin in patients with otherwise unexplained hemolytic anemia. This series shows the enormous utility of using molecular techniques for diagnosis.

Robot-Assisted Stereotactic Shunting as a Novel Treatment for Pontine Glioependymal Cysts

2021 ◽  
Author(s):  
Simon Schieferdecker ◽  
Stefan Hunsche ◽  
Faycal El Majdoub ◽  
Mohammad Maarouf
Keyword(s):  
Abducens Nerve ◽  
Ependymal Cells ◽  
Robot Assisted ◽  
Quick Recovery ◽  
Glioependymal Cyst ◽  
Novel Treatment ◽  
First Case ◽  
Mri Scans ◽  
The Central Nervous System ◽  
Magnetic Resonance Imaging Mri

AbstractIn this case report, the authors describe the first case of a glioependymal cyst of the brainstem managed by robot-assisted, stereotactic, cysto-ventricular shunting. Glioependymal cysts are rare congenital cystic lesions that are thought to form by displacement of ependymal cells during the embryonal period. Glioependymal cysts have been reported in a variety of different locations within the central nervous system. However, glioependymal cysts of the brainstem have only been described once before. Here, we report the case of a 53-year-old man who was referred to our department due to hemiparesis, hemihypesthesia, and hemidysesthesia, as well as facial and abducens nerve palsy. A large pontine glioependymal cyst was confirmed via magnetic resonance imaging (MRI) scans. The cyst was subsequently decompressed by connecting the cyst with the fourth ventricle via robot-assisted stereotactic shunt placement. In the postoperative course, the patient made a quick recovery and did not report any permanent neurologic deficits.

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