Hemophiliacs A patients from Algeria without mutation or rearrangement in the F8 gene

2022 ◽  
Vol 11 (6) ◽  
pp. 685-689
Author(s):  
Abdi Meriem ◽  
Zemani-Fodil Faouzia
Keyword(s):  
Dna Methylation ◽  
Hemophilia A ◽  
Point Mutations ◽  
Bleeding Disorder ◽  
Healthy Controls ◽  
Epigenetic Mechanisms ◽  
Intron 1 ◽  
Western Algeria ◽  
Molecular Origin

Hemophilia A (HA) is the most severe X-linked inherited bleeding disorder caused by hemizygous mutations in the F8 gene. Several F8 mutations are responsible of HA including intron 1 and 22 micro-inversions, large and small deletions, insertions, duplications, and point mutations. In a previous study, we determined the molecular causes of HA in 85% of patients group studied. However, no mutation were found in three unrelated patients origi-nating from Western Algeria. In the present study, we sought to characterize the molecular origin of HA in three patients by investigating rearrangements in the F8 gene using the MLPA method. Comparaison between case results and healthy controls showed absence of deletions or duplications in the F8 gene in these three hemophiliacs A patients. This finding has already been reported in many studies where any F8 mutation or rearrangement has been identified. Further analysis are required in order to determine the molecular origin of the disease in these families. It would be very interesting to look for deep intonic mutations and to study epigenetic mechanisms as well as DNA methylation and miRNAs.

Description of a Large Duplication in F8 Gene Responsible for Severe Hemophilia A.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1149-1149
Author(s):  
Christine Vinciguerra ◽  
Jenny Goudemand ◽  
Christophe Zawadzki ◽  
Dorothee Pellecchia ◽  
Claude Negrier
Keyword(s):  
Factor Viii ◽  
Quantitative Method ◽  
Hemophilia A ◽  
High Titer ◽  
Genetic Disorders ◽  
Point Mutations ◽  
Genetic Mutation ◽  
Severe Hemophilia ◽  
Intron 1 ◽  
Large Rearrangements

Abstract Hemophilia A is a common inherited bleeding disorder, caused by factor VIII (FVIII) deficiency as a result of mutations in the factor VIII gene (F8 gene). Intron 1 and 22 inversions, small insertions/deletions and point mutations are the most common genetic defects responsible for severe hemophilia A. However, a F8 gene mutation is not found in 2–5% of patients with severe hemophilia A (FVIII:C<1IU/dL). Large rearrangements are frequent in other genetic disorders and only one case of exon 13 duplication was described in a patient with mild hemophilia (Casula et al, Blood 1990). We described here a large duplication in F8 gene in a CRM− patient with severe hemophilia A: (FVIII:C < 1 UI/dL, FVIII:Ag < 1%) who developed a high-titer inhibitor (peak 10 BU). A previous investigation did not find intron 1 and 22 inversion or exons /splice sites sequencing abnormalities. The promoter region was also sequenced, but no genetic mutation was then characterized. The duplication was detected by MP/LC (Multiplex PCR/Liquid chromatography) which is a quantitative method able to detect large rearrangements. Initially described by Dehainault et al (Nucl Acids Res 2004) in retinoblastoma patients, this method showed that a duplication affected a large part of F8 gene, e.g. the 3′ part of intron 10, exons 11 to 14 and a part of intron 14. To our knowledge, this is the first duplication responsible for severe hemophila A described so far. This finding suggests that the detection of large rearrangements with quantitative method as MP/LC, QMPSF or MLPA would be useful in hemophilic patients where the screening for inversions or genetic events in the coding regions are unsuccessful. This kind of large gene modifications may indeed account for at least some of the 2–5% cases where the coding sequence does not appeared to be altered. In this case, the truncation of the primary polypeptide sequence did not result in any secretion of the FVIII protein, that may have increased the risk of inhibitor development.

A Simple Enzyme-Immunoassay (EIA) Test for Factor VIII-Related Antigen (VIIIAGN)

1979 ◽  
Vol 42 (03) ◽  
pp. 848-854 ◽  
Author(s):  
Paul M Ness ◽  
Herbert A Perkins
Keyword(s):  
Factor Viii ◽  
Enzyme Immunoassay ◽  
Hemophilia A ◽  
Single Sample ◽  
Healthy Controls ◽  
Von Willebrand's Disease ◽  
Factor Viii Related Antigen ◽  
Von Willebrand’S Disease ◽  
Increased Sensitivity

SummaryAn enzyme immunoassay (EIA) system has been developed to measure factor VIII- related antigen (VIIIAGN). This assay gives similar results to the commonly used Laurell electroimmunodiffusion (EID) assay for VIIIAGN as shown by comparison of both techniques with samples from healthy controls, patients with hemophilia A, and patients with von Willebrand’s disease. The assay also has a greater precision than the EID technique as demonstrated by multiple assays of aliquots of a single sample. The use of this EIA test for VIIIAGN is simple and employs inexpensive reagents and equipment. The use of expensive antisera is minimized. EIA for VIIIAGN has the advantage of increased sensitivity compared to Laurell EIA.

Epigenetic Mechanisms of Maternal Dietary Protein and Amino Acids Affecting Growth and Development of Offspring

2019 ◽  
Vol 20 (7) ◽  
pp. 727-735 ◽  
Author(s):  
Yi Wu ◽  
Zhibin Cheng ◽  
Yueyu Bai ◽  
Xi Ma
Keyword(s):  
Amino Acids ◽  
Dna Methylation ◽  
Dietary Protein ◽  
Growth And Development ◽  
Later Life ◽  
Biological Macromolecules ◽  
Epigenetic Mechanisms ◽  
Maternal Circulation ◽  
Energy Processing ◽  
Living Organisms

Nutrients can regulate metabolic activities of living organisms through epigenetic mechanisms, including DNA methylation, histone modification, and RNA regulation. Since the nutrients required for early embryos and postpartum lactation are derived in whole or in part from maternal and lactating nutrition, the maternal nutritional level affects the growth and development of fetus and creates a profound relationship between disease development and early environmental exposure in the offspring’s later life. Protein is one of the most important biological macromolecules, involved in almost every process of life, such as information transmission, energy processing and material metabolism. Maternal protein intake levels may affect the integrity of the fetal genome and alter DNA methylation and gene expression. Most amino acids are supplied to the fetus from the maternal circulation through active transport of placenta. Some amino acids, such as methionine, as dietary methyl donor, play an important role in DNA methylation and body’s one-carbon metabolism. The purpose of this review is to describe effects of maternal dietary protein and amino acid intake on fetal and neonatal growth and development through epigenetic mechanisms, with examples in humans and animals.

Epigenetics, Nutrition, Disease and Drug Development

2019 ◽  
Vol 16 (4) ◽  
pp. 386-391 ◽  
Author(s):  
Kenneth Lundstrom
Keyword(s):  
Dna Methylation ◽  
Drug Discovery ◽  
Rna Interference ◽  
Nutritional Requirements ◽  
Signal Pathways ◽  
Disease Development ◽  
Epigenetic Mechanisms ◽  
Epigenetic Changes ◽  
Health And Disease ◽  
Novel Drug

Epigenetic mechanisms comprising of DNA methylation, histone modifications and gene silencing by RNA interference have been strongly linked to the development and progression of various diseases. These findings have triggered research on epigenetic functions and signal pathways as targets for novel drug discovery. Dietary intake has also presented significant influence on human health and disease development and nutritional modifications have proven important in prevention, but also the treatment of disease. Moreover, a strong link between nutrition and epigenetic changes has been established. Therefore, in attempts to develop novel safer and more efficacious drugs, both nutritional requirements and epigenetic mechanisms need to be addressed.

scholarly journals New Aspects of the Epigenetics of Pancreatic Carcinogenesis

Epigenomes ◽  
2020 ◽  
Vol 4 (3) ◽  
pp. 18
Author(s):  
Murat Toruner ◽  
Martin E. Fernandez-Zapico ◽  
Christopher L. Pin
Keyword(s):  
Pancreatic Cancer ◽  
Dna Methylation ◽  
Survival Rate ◽  
Epigenetic Mechanisms ◽  
Therapeutic Approaches ◽  
Cancer Epigenetics ◽  
Pancreatic Carcinogenesis ◽  
New Therapeutic Approaches ◽  
Environmental Events ◽  
Underlying Pathogenesis

Pancreatic cancer remains among the deadliest forms of cancer with a 5 year survival rate less than 10%. With increasing numbers being observed, there is an urgent need to elucidate the pathogenesis of pancreatic cancer. While both contribute to disease progression, neither genetic nor environmental factors completely explain susceptibility or pathogenesis. Defining the links between genetic and environmental events represents an opportunity to understand the pathogenesis of pancreatic cancer. Epigenetics, the study of mitotically heritable changes in genome function without a change in nucleotide sequence, is an emerging field of research in pancreatic cancer. The main epigenetic mechanisms include DNA methylation, histone modifications and RNA interference, all of which are altered by changes to the environment. Epigenetic mechanisms are being investigated to clarify the underlying pathogenesis of pancreatic cancer including an increasing number of studies examining the role as possible diagnostic and prognostic biomarkers. These mechanisms also provide targets for promising new therapeutic approaches for this devastating malignancy.

scholarly journals DNA Methylation Profiling for the Diagnosis and Prognosis of Patients with Nontuberculous Mycobacterium Lung Disease

2021 ◽  
Vol 43 (2) ◽  
pp. 501-512
Author(s):  
Jee Youn Oh ◽  
Young Kyung Ko ◽  
Jeong-An Gim
Keyword(s):  
Dna Methylation ◽  
Lung Disease ◽  
Poor Prognosis ◽  
Wnt Signaling Pathway ◽  
Fold Change ◽  
Nontuberculous Mycobacterium ◽  
Healthy Controls ◽  
Log2 Fold Change ◽  
Diagnosis And Prognosis ◽  
Ntm Lung Disease

The incidence of nontuberculous Mycobacterium (NTM) lung disease is rapidly increasing; however, its diagnosis and prognosis remain unclear while selecting patients who will respond to appropriate treatment. Differences in DNA methylation patterns between NTM patients with good or poor prognosis could provide important therapeutic targets. We used the Illumina MethylationEPIC (850k) DNA methylation microarray to determine the pattern between differentially methylated regions (DMRs) in NTM patients with good or poor prognosis (n = 4/group). Moreover, we merged and compared 20 healthy controls from previous Illumina Methylation450k DNA methylation microarray data. We selected and visualized the DMRs in the form of heatmaps, and enriched terms associated with these DMRs were identified by functional annotation with the “pathfinder” package. In total, 461 and 293 DMRs (|Log2 fold change| > 0.1 and p < 0.03) were more methylated in patients with four poor and four good prognoses, respectively. Furthermore, 337 and 771 DMRs (|Log2 fold change| > 0.08 and p < 0.001) were more methylated in eight NTM patients and 20 healthy controls, respectively. TGFBr1 was significantly less methylated, whereas HLA-DR1 and HLA-DR5 were more methylated in patients with poor prognosis (compared to those with good prognosis). LRP5, E2F1, and ADCY3 were the top three less-methylated genes in NTM patients (compared with the controls). The mTOR and Wnt signaling pathway-related genes were less methylated in patients with NTM. Collectively, genes related to Th1-cell differentiation, such as TGFBr1 and HLA-DR, may be used as biomarkers for predicting the treatment response in patients with NTM lung disease.

scholarly journals Altered DNA methylation pattern reveals epigenetic regulation of Hox genes in thoracic aortic dissection and serves as a biomarker in disease diagnosis

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Peiru Liu ◽  
Jing Zhang ◽  
Duo Du ◽  
Dandan Zhang ◽  
Zelin Jin ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Aortic Dissection ◽  
Epigenetic Regulation ◽  
Heart Development ◽  
Type A ◽  
Methylation Pattern ◽  
Healthy Controls ◽  
Global Methylation ◽  
Thoracic Aortic Dissection

Abstract Background Thoracic aortic dissection (TAD) is a severe disease with limited understandings in its pathogenesis. Altered DNA methylation has been revealed to be involved in many diseases etiology. Few studies have examined the role of DNA methylation in the development of TAD. This study explored alterations of the DNA methylation landscape in TAD and examined the potential role of cell-free DNA (cfDNA) methylation as a biomarker in TAD diagnosis. Results Ascending aortic tissues from TAD patients (Stanford type A; n = 6) and healthy controls (n = 6) were first examined via whole-genome bisulfite sequencing (WGBS). While no obvious global methylation shift was observed, numerous differentially methylated regions (DMRs) were identified, with associated genes enriched in the areas of vasculature and heart development. We further confirmed the methylation and expression changes in homeobox (Hox) clusters with 10 independent samples using bisulfite pyrosequencing and quantitative real-time PCR (qPCR). Among these, HOXA5, HOXB6 and HOXC6 were significantly down-regulated in TAD samples relative to controls. To evaluate cfDNA methylation pattern as a biomarker in TAD diagnosis, cfDNA from TAD patients (Stanford type A; n = 7) and healthy controls (n = 4) were examined by WGBS. A prediction model was built using DMRs identified previously from aortic tissues on methylation data from cfDNA. Both high sensitivity (86%) and specificity (75%) were achieved in patient classification (AUC = 0.96). Conclusions These findings showed an altered epigenetic regulation in TAD patients. This altered epigenetic regulation and subsequent altered expression of genes associated with vasculature and heart development, such as Hox family genes, may contribute to the loss of aortic integrity and TAD pathogenesis. Additionally, the cfDNA methylation in TAD was highly disease specific, which can be used as a non-invasive biomarker for disease prediction.

scholarly journals Androgenic-Induced Transposable Elements Dependent Sequence Variation in Barley

2021 ◽  
Vol 22 (13) ◽  
pp. 6783
Author(s):  
Renata Orłowska ◽  
Katarzyna A. Pachota ◽  
Wioletta M. Dynkowska ◽  
Agnieszka Niedziela ◽  
Piotr T. Bednarek
Keyword(s):  
Dna Methylation ◽  
Transposable Elements ◽  
Dna Sequence ◽  
Sequence Variation ◽  
Nuclear Dna ◽  
Point Mutations ◽  
Mobile Elements ◽  
Dna Demethylation ◽  
Plant Genome

A plant genome usually encompasses different families of transposable elements (TEs) that may constitute up to 85% of nuclear DNA. Under stressful conditions, some of them may activate, leading to sequence variation. In vitro plant regeneration may induce either phenotypic or genetic and epigenetic changes. While DNA methylation alternations might be related, i.e., to the Yang cycle problems, DNA pattern changes, especially DNA demethylation, may activate TEs that could result in point mutations in DNA sequence changes. Thus, TEs have the highest input into sequence variation (SV). A set of barley regenerants were derived via in vitro anther culture. High Performance Liquid Chromatography (RP-HPLC), used to study the global DNA methylation of donor plants and their regenerants, showed that the level of DNA methylation increased in regenerants by 1.45% compared to the donors. The Methyl-Sensitive Transposon Display (MSTD) based on methylation-sensitive Amplified Fragment Length Polymorphism (metAFLP) approach demonstrated that, depending on the selected elements belonging to the TEs family analyzed, varying levels of sequence variation were evaluated. DNA sequence contexts may have a different impact on SV generated by distinct mobile elements belonged to various TE families. Based on the presented study, some of the selected mobile elements contribute differently to TE-related SV. The surrounding context of the TEs DNA sequence is possibly important here, and the study explained some part of SV related to those contexts.

scholarly journals Epigenetic Modifications During Sex Change Repress Gonadotropin Stimulation of Cyp19a1a in a Teleost Ricefield Eel (Monopterus albus)

Endocrinology ◽  
2013 ◽  
Vol 154 (8) ◽  
pp. 2881-2890 ◽  
Author(s):  
Yang Zhang ◽  
Shen Zhang ◽  
Zhixin Liu ◽  
Lihong Zhang ◽  
Weimin Zhang
Keyword(s):  
Dna Methylation ◽  
Binding Protein ◽  
Sex Change ◽  
Gonadal Development ◽  
Proximal Region ◽  
Histone Deacetylation ◽  
Epigenetic Mechanisms ◽  
Gonadal Differentiation ◽  
Stimulation Of

Abstract In vertebrates, cytochrome P450 aromatase, encoded by cyp19a1, converts androgens to estrogens and plays important roles in gonadal differentiation and development. The present study examines whether epigenetic mechanisms are involved in cyp19a1a expression and subsequent gonadal development in the hermaphroditic ricefield eel. The expression of the ricefield eel cyp19a1a was stimulated by gonadotropin via the cAMP pathway in the ovary but not the ovotestis or testis. The CpG within the cAMP response element (CRE) of the cyp19a1a promoter was hypermethylated in the ovotestis and testis compared with the ovary. The methylation levels of CpG sites around CRE in the distal region (region II) and around steroidogenic factor 1/adrenal 4 binding protein sites and TATA box in the proximal region (region I) were inversely correlated with cyp19a1a expression during the natural sex change from female to male. In vitro DNA methylation decreased the basal and forskolin-induced activities of cyp19a1a promoter. Chromatin immunoprecipitation assays indicated that histone 3 (Lys9) in both regions I and II of the cyp19a1a promoter were deacetylated and trimethylated in the testis, and in contrast to the ovary, phosphorylated CRE-binding protein failed to bind to these regions. Lastly, the DNA methylation inhibitor 5-aza-2′-deoxycytidine reversed the natural sex change of ricefield eels. These results suggested that epigenetic mechanisms involving DNA methylation and histone deacetylation and methylation may abrogate the stimulation of cyp19a1a by gonadotropins in a male-specific fashion. This may be a mechanism widely used to drive natural sex change in teleosts as well as gonadal differentiation in other vertebrates.

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