Interchromosomal Associations that Alter Nf1 Gene Expression can Modify Clinical Manifestations of Neurofibromatosis 1

2008 ◽  
Author(s):  
Andrew R. Hoffman
Keyword(s):  
Gene Expression ◽  
Clinical Manifestations ◽  
Neurofibromatosis 1 ◽  
Nf1 Gene

Loss of neurofibromatosis 1 (NF1 ) gene expression in NF1-associated pilocytic astrocytomas

2000 ◽  
Vol 26 (4) ◽  
pp. 361-367 ◽  
Author(s):  
D. H. Gutmann ◽  
J. Donahoe ◽  
T. Brown ◽  
C. D. James ◽  
A. Perry
Keyword(s):  
Gene Expression ◽  
Neurofibromatosis 1 ◽  
Pilocytic Astrocytomas ◽  
Nf1 Gene

HIF1-α-Mediated Gene Expression Induced by Vitamin B1 Deficiency

2013 ◽  
Vol 83 (3) ◽  
pp. 188-197 ◽  
Author(s):  
Rebecca L. Sweet ◽  
Jason A. Zastre
Keyword(s):  
Gene Expression ◽  
Thiamine Deficiency ◽  
Glucose Transporter ◽  
Neuroblastoma Cell ◽  
Hypoxia Inducible Factor ◽  
Clinical Manifestations ◽  
Vitamin B1 ◽  
Low Oxygen ◽  
Glucose Transporter 1 ◽  
Metabolic Intermediates

It is well established that thiamine deficiency results in an excess of metabolic intermediates such as lactate and pyruvate, which is likely due to insufficient levels of cofactor for the function of thiamine-dependent enzymes. When in excess, both pyruvate and lactate can increase the stabilization of the hypoxia-inducible factor 1-alpha (HIF-1α) transcription factor, resulting in the trans-activation of HIF-1α regulated genes independent of low oxygen, termed pseudo-hypoxia. Therefore, the resulting dysfunction in cellular metabolism and accumulation of pyruvate and lactate during thiamine deficiency may facilitate a pseudo-hypoxic state. In order to investigate the possibility of a transcriptional relationship between hypoxia and thiamine deficiency, we measured alterations in metabolic intermediates, HIF-1α stabilization, and gene expression. We found an increase in intracellular pyruvate and extracellular lactate levels after thiamine deficiency exposure to the neuroblastoma cell line SK-N-BE. Similar to cells exposed to hypoxia, there was a corresponding increase in HIF-1α stabilization and activation of target gene expression during thiamine deficiency, including glucose transporter-1 (GLUT1), vascular endothelial growth factor (VEGF), and aldolase A. Both hypoxia and thiamine deficiency exposure resulted in an increase in the expression of the thiamine transporter SLC19A3. These results indicate thiamine deficiency induces HIF-1α-mediated gene expression similar to that observed in hypoxic stress, and may provide evidence for a central transcriptional response associated with the clinical manifestations of thiamine deficiency.

Thirty-Nine Novel Neurofibromatosis 1 (NF1)Gene Mutations Identified in Slovak Patients

2013 ◽  
Vol 77 (5) ◽  
pp. 364-379 ◽  
Author(s):  
Martina Nemethova ◽  
Anna Bolcekova ◽  
Denisa Ilencikova ◽  
Darina Durovcikova ◽  
Katarina Hlinkova ◽  
...  
Keyword(s):  
Gene Mutations ◽  
Neurofibromatosis 1 ◽  
Nf1 Gene

scholarly journals HIF-Mediated and Non-HIF-Mediated Differential Gene Expressions in Sickle Cell Reticulocyte and Their Impact on Clinical Manifestations

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 950-950
Author(s):  
Xu Zhang ◽  
Jihyun Song ◽  
Binal N. Shah ◽  
Jin Han ◽  
Taif Hassan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Differentially Expressed Genes ◽  
Research Funding ◽  
Clinical Manifestations ◽  
Hemoglobin Concentration ◽  
Differentially Expressed ◽  
Erythroid Progenitors ◽  
Advisory Committees ◽  
Deconvolution Analysis ◽  
Stress Erythropoiesis

Abstract Reticulocytosis in sickle cell disease (SCD) is driven by tissue hypoxia from hemolytic anemia and vascular occlusion. Gene expression changes caused by hypoxia and other factors during reticulocytosis may impact SCD outcomes. We detected 1226 differentially expressed genes in SCD reticulocyte transcriptome compared to normal Black controls. To assess the role of hypoxia-mediating HIFs from other regulation of changes of the SCD reticulocyte transcriptome, we compared differential expression in SCD to that in Chuvash erythrocytosis (CE), a disorder characterized by constitutive upregulation of HIFs in normoxia. Of the SCD differentially expressed genes, 28% were shared between CE and SCD and thus classified as HIF-mediated. The HIF-mediated changes were generally in genes promoting erythroid maturation. We found that genes encoding the response to endoplasmic reticulum stress generally lacked HIF mediation. We then investigated the clinical correlation of erythroid gene expression for the 1226 differentially expressed genes detected in SCD reticulocytes, using clinical measures and gene expression data previously profiled in peripheral blood mononuclear cells (PBMCs) of 157 SCD patients at the University of Illinois at Chicago (UIC). Normal PBMCs contain only a small number of erythroid progenitors, but in SCD or CE PBMCs the erythroid transcriptome is enriched due to elevated circulating erythroid progenitors from heightened erythropoiesis (PMID: 32399971). We applied deconvolution analysis to assess the clinical correlation of erythroid gene expression, using a 16-gene expression signature of erythroid progenitors previously identified in SCD PBMCs. Deconvolution analysis uses the proportion of cell/tissue or specific marker genes (here the erythroid specific 16-gene signature) to dissect gene expression variation in biological samples with cell/tissue type heterogeneity. We correlated, in the 157 UIC patients, erythroid gene expression with i) degree of anemia as indicated by hemoglobin concentration, ii) vaso-occlusive severe pain episodes per year, and iii) degree of hemolysis measured by a hemolysis index. The analysis identified 231 genes associated with at least one of the complications. Increased expression of 40 erythroid specific genes, including 15 HIF-mediated genes, was associated with all three complications. These 40 genes are all upregulated in SCD reticulocytes and correlated with low hemoglobin concentration, frequent severe pain episodes, and high hemolysis index, suggesting that these manifestations may share a relationship to stress erythropoiesis-driven transcriptional activity. Expression quantitative trait loci (eQTL) contain genetic polymorphisms that associate with gene expression level, which can be viewed as a natural experiment to investigate the causal relations between gene expression change and phenotypic outcomes. To assess the causal effect of erythroid gene expression, we tested association between erythroid eQTL and the clinical manifestations in 906 SCD patients from the Walk-PHaSST and PUSH cohorts. We first mapped erythroid eQTL in the 157 UIC patients, who were previously genotyped by array, applying deconvolution algorithm on the same PBMC data for the 1226 differential genes in SCD reticulocytes, and detected 54 distinct eQTL for 30 genes at 5% false discovery rate. After adjusting for multiple comparisons, we found that the C allele of rs16911905, located in the β-globin cluster and associated with increased erythroid expression of HBD (encodes δ-globin of hemoglobin A 2), significantly correlated with lower hemoglobin concentration (β=-0.064, 95% CI -0.092 - -0.036, P=6.7×10 -6). The C allele was also associated with higher hemolytic rate (P=0.031), less frequent pain episodes (P=0.045), and increased erythroid expression of HBB here encoding sickle β-globin (P=5.1x10 -5). The association of the C allele with lower hemoglobin concentration was then validated in 242 patients from the UIC cohort (β=-0.071, 95% CI -0.13 - -0.011, P=0.023), as was the trend of association with higher hemolytic rate (P=0.0031) and less pain episodes (P=0.034). Our findings reveal HIF- and non-HIF-mediated genes in SCD stress erythropoiesis, and identify novel clinical associations for a HBD eQTL. Our study highlights the correlation of altered erythroid gene expression with SCD hemolytic and vaso-occlusive manifestations. Disclosures Saraf: Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding. Gordeuk: Modus Therapeutics: Consultancy; Novartis: Research Funding; Incyte: Research Funding; Emmaus: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; CSL Behring: Consultancy.

scholarly journals Expression of the apoptosis-releated genes in patients with newly diagnosed chronic lymphocytic leukemia in clinical data context

2018 ◽  
Vol 17 (2) ◽  
pp. 41-46 ◽  
Author(s):  
S. G. Zakharov ◽  
A. K. Golenkov ◽  
A. V. Misyurin ◽  
E. V. Kataeva ◽  
A. A. Rudakova ◽  
...  
Keyword(s):  
Gene Expression ◽  
Clinical Manifestations ◽  
Multivariate Regression Analysis ◽  
Lymphocytic Leukemia ◽  
Newly Diagnosed ◽  
Expression Of Genes ◽  
Gene Level ◽  
Genes Encoding ◽  
Group Ii ◽  
High Level

Introduction.The given data of fundamental studies of apoptosis processes in B-cell lymphocytic leukemia (B-CLL) testifies about the complexity and variety of mechanisms affecting the kinetics of normal cells and tumor lymphocytes in this disease. It is important to study the severity of clinical manifestations of the disease depending on the expression of the genes that modulate apoptosis.The purposeof the study is to compare the activity of genes encoding apoptosis modulators, the cell cycle and cancer-testicular PRAME protein with clinical manifestations of the disease in primary patients with B-CLL.Materials and methods.The level of expression of the proapoptotic genes FAS, TRAIL, TNFR2, DR4/5 and DR3, as well as the HSP27, XIAP genes, blocking apoptosis was determined in 23 patients with newly diagnosed chronic B-CLL. In addition, expression of genes TP53 and P21 and cancer-testis gene PRAME are tested.Results.According to the multivariate regression analysis, the FAS gene expression in the onset of the disease had the greatest impact on the clinical characteristics of the disease. In this connection, the patients were divided into groups with normal (group) and low gene level (group II). A low level of FAS expression (Me 387 %) was associated with stage II disease (p = 0.03), a large number of lympho cytes (p = 0.001), fewer erythrocytes (p = 0.08), and a lower level of TNFR2 gene expression (p = 0.08), high level of expression of XIAP, HSP27, P21. Overall, the anti-apoptotic potential in Group II patients was higher, which was accompanied by more pronounced clinical manifestations of the disease.Conclusions.The increased anti-apoptotic potential of tumor lymphocytes in newly diagnosed B-CLL is accompanied by a larger tumor mass and greater clinical and hematological manifestation of the disease.

Dural Ectasia in Neurofibromatosis 1: Case Series, Management, and Review

Neurosurgery ◽  
2019 ◽  
Vol 86 (5) ◽  
pp. 646-655
Author(s):  
Sean P Polster ◽  
Mark C Dougherty ◽  
Hussein A Zeineddine ◽  
Seán B Lyne ◽  
Heather L Smith ◽  
...  
Keyword(s):  
Natural History ◽  
Clinical Course ◽  
Treatment Options ◽  
Plexiform Neurofibroma ◽  
Clinical Manifestations ◽  
Case Series ◽  
Neurofibromatosis 1 ◽  
Dural Ectasia ◽  
Asymptomatic Patients ◽  
Nonsurgical Patients

Abstract BACKGROUND The natural history and management of dural ectasia in Neurofibromatosis 1 (NF1) is still largely unknown. Dural ectasias are one of the common clinical manifestations of NF1; however, the treatment options for dural ectasias remain unstudied. OBJECTIVE To investigate the natural history, diagnosis, management, and outcome of the largest case series of patients with NF1-associated dural ectasia to date. METHODS Records from our NF1 clinic were reviewed to identify NF1 patients with computed tomography or magnetic resonance imaging evidence of dural ectasia(s) to determine their clinical course. Demographics, symptoms, radiographic and histopathologic findings, treatment, and clinical course were assessed. RESULTS Thirty-four of 37 patients were managed without surgery. Of the 18 initially asymptomatic patients, 5 (27.8%) progressed to symptoms attributable to a dural ectasia (onset of 2.7% per patient-year). Three patients required surgical intervention because of extraspinal mass effect. All 3 initially improved but had symptom recurrence within 2 yr. Reoperation involved shunt placement for cerebrospinal fluid (CSF) diversion. On imaging review, 26 (76.5%) of the nonsurgical patients harbored an associated nearby plexiform neurofibroma. Pathology of one surgical case revealed dural infiltration by diffuse neurofibroma. CONCLUSION Using the largest NF1-associated dural ectasia group to date, we report the first symptom-onset rate for nonsurgical patients. In the few cases requiring surgery for decompression, primary resection, and patching of ectasias failed, subsequently requiring CSF shunting. We demonstrate imaging evidence of nearby plexiform neurofibroma in a majority of cases, which, when combined with histopathology, provides a novel explanation for the formation of dural ectasias.

scholarly journals Polymorphisms of MFGE8 are associated with susceptibility and clinical manifestations through gene expression modulation in Koreans with systemic lupus erythematosus

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Wook-Young Baek ◽  
Ji-Min Woo ◽  
Hyoun-Ah Kim ◽  
Ju-Yang Jung ◽  
Chang-Hee Suh
Keyword(s):  
Gene Expression ◽  
Systemic Lupus Erythematosus ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Milk Fat ◽  
Clinical Manifestations ◽  
Αvβ3 Integrin ◽  
Apoptotic Cells ◽  
Systemic Lupus ◽  
Dsdna Antibody

AbstractSystemic lupus erythematosus (SLE) is characterized by impaired clearance of apoptotic cells. Milk fat globule epidermal growth factor 8 (MFGE8) is a protein that connects αvβ3 integrin on phagocytic macrophages with phosphatidylserine on apoptotic cells. We investigated whether genetic variation of the MFGE8 gene and serum MFGE8 concentration are associated with SLE. Single nucleotide polymorphisms (SNPs) were genotyped and serum concentrations were analyzed. The rs2271715 C allele and rs3743388 G allele showed higher frequency in SLE than in healthy subjects (HSs). Three haplotypes were found among 4 SNPs (rs4945, rs1878327, rs2271715, and rs3743388): AACG, CGCG, and CGTC. CGCG haplotype was significantly more common in SLE than in HSs. rs4945 was associated with the erythrocyte sedimentation rate and rs1878327 was associated with alopecia, C-reactive protein, complement 3, anti-dsDNA antibody, and high disease activity. rs2271715 and rs3743388 were associated with renal disease, cumulative glucocorticoid dose, and cyclophosphamide and mycophenolate mofetil use. Serum MFGE8 concentrations were significantly higher in SLE than in HSs. Furthermore, the levels of MFGE8 were significantly higher in SLE than HSs of the rs2271715 CC genotype. In conclusion, MFGE8 genetic polymorphisms are associated not only with susceptibility to SLE but also with disease activity through modulation of gene expression.

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