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Françoise Bernaudin, Cécile Arnaud, Annie Kamdem, Isabelle Hau, Françoise Lelong, Ralph Epaud, Corinne Pondarré, Serge Pissard
Sickle cell anemia (SCA), albeit monogenic, has heterogeneous phenotypic expression, mainly related to the level of hemoglobin F (HbF). No large cohort studies have ever compared biological parameters in patients with major β-globin haplotypes; ie, Senegal (SEN), Benin (BEN), and Bantu/Central African Republic (CAR). The aim of this study was to evaluate the biological impact of α genes, β haplotypes, and glucose-6-phosphate dehydrogenase (G6PD) activity at baseline and with hydroxyurea (HU). Homozygous HbS patients from the Créteil pediatric cohort with available α-gene and β-haplotype data were included (n = 580; 301 females and 279 males) in this retrospective study...
March 27, 2018: Blood Advances
Nanjela Chindima, Panji Nkhoma, Musalula Sinkala, Mildred Zulu, Doris Kafita, Marah Simakando, Florence Mwaba, Hamakwa Mantina, Mubanga Mutale
Context: Sickle cell disease is a group of hemoglobin (Hb) disorders resulting from the inheritance of the sickle β-globin gene. It is the most common pathological Hb mutation worldwide with 75% being born in Sub-Saharan Africa. Aims: This study aims to determine if dried blood spots (DBSs) can be used for diagnosis of sickle cell in newborns. In Zambia, there is no neonatal screening program for sickle cell anemia (SCA), yet it has been proved that early diagnosis by newborn screening (NBS) using DBSs and access to comprehensive care results in survival to adulthood of over 96% of sickle cell patients...
January 2018: International Journal of Applied and Basic Medical Research
Sarinthip Preedagasamzin, Tiwaporn Nualkaew, Tanjitti Pongrujikorn, Natini Jinawath, Ryszard Kole, Suthat Fucharoen, Natee Jearawiriyapaisarn, Saovaros Svasti
Repair of a splicing defect of β-globin pre-mRNA harboring hemoglobin E (HbE) mutation was successfully accomplished in erythroid cells from patients with β-thalassemia/HbE disorder by a synthetic splice-switching oligonucleotide (SSO). However, its application is limited by short-term effectiveness and requirement of lifelong periodic administration of SSO, especially for chronic diseases like thalassemias. Here, we engineered lentiviral vectors that stably express U7 small nuclear RNA (U7 snRNA) carrying the splice-switching sequence of the SSO that restores correct splicing of βE -globin pre-mRNA and achieves a long-term therapeutic effect...
March 14, 2018: Biochemical and Biophysical Research Communications
Min Young Kim, Ji Sook Kim, Seung Han Son, Chang Su Lim, Hea Young Eum, Dae Hyun Ha, Mi Ae Park, Eun Jung Baek, Buom-Yong Ryu, Ho Chul Kang, Vladimir N Uversky, Chul Geun Kim
During hematopoiesis, red blood cells originate from the hematopoietic stem cell reservoir. Although the regulation of erythropoiesis and globin expression has been intensively investigated, the underlining mechanisms are not fully understood, including the interplay between transcription factors and epigenetic factors. Here, we uncover that the Mbd2-free NuRD chromatin remodeling complex potentiates erythroid differentiation of proerythroblasts via managing functions of the CP2c complexes. We found that both Mbd2 and Mbd3 expression is downregulated during differentiation of MEL cells in vitro and in normal erythropoiesis in mouse bone marrow, and Mbd2 downregulation is crucial for erythropoiesis...
March 14, 2018: Nucleic Acids Research
Gregory J Kato, Frédéric B Piel, Clarice D Reid, Marilyn H Gaston, Kwaku Ohene-Frempong, Lakshmanan Krishnamurti, Wally R Smith, Julie A Panepinto, David J Weatherall, Fernando F Costa, Elliott P Vichinsky
Sickle cell disease (SCD) is a group of inherited disorders caused by mutations in HBB, which encodes haemoglobin subunit β. The incidence is estimated to be between 300,000 and 400,000 neonates globally each year, the majority in sub-Saharan Africa. Haemoglobin molecules that include mutant sickle β-globin subunits can polymerize; erythrocytes that contain mostly haemoglobin polymers assume a sickled form and are prone to haemolysis. Other pathophysiological mechanisms that contribute to the SCD phenotype are vaso-occlusion and activation of the immune system...
March 15, 2018: Nature Reviews. Disease Primers
Atulabh Vajpeyee, Teddy Wijatmiko, Manisha Vajpeyee, Onjal Taywade
Purpose: Several blood markers have been evaluated in stroke patients, but their role remains limited in clinical practice. This study was designed to evaluate the utility of cell free DNA (cf DNA) in stroke patients undergoing therapeutic intervention in the form of mechanical thrombectomy in acute ischemic stroke patients. Materials and Methods: Twenty-six patients with ischemic stroke who were managed with interventions like intravenous thrombolysis (IVT) and mechanical thrombectomy were recruited consecutively in this study...
March 2018: Neurointervention
Ashraf Brik, Roman Meledin, Sachitanand Mali, Oded Kleifeld
We report a general and novel semisynthetic strategy for the preparation of ubiquitinated protein activity based probes applying sequential dehydroalanine formation on expressed proteins. We applied this approach to construct physiologically and therapeutically relevant ubiquitinated α-globin probe, which was used for the enrichment and proteomic identification of α-globin modulating deubiquitinases. We found USP15 as a potential deubiquitinase, modulating α-globin, which excess aggravates beta-thalassemia symptoms...
March 12, 2018: Angewandte Chemie
Naoya Uchida, Juan J Haro-Mora, Selami Demirci, Atsushi Fujita, Lydia Raines, Matthew M Hsieh, John F Tisdale
A reliable cell line capable of robust in vitro erythroid differentiation would be useful to investigate red blood cell (RBC) biology and genetic strategies for RBC diseases. K562 cells are widely utilized for erythroid differentiation; however, current differentiation methods are insufficient to analyze globin proteins. In this study, we sought to improve erythroid differentiation from K562 cells to enable protein-level globin analysis. K562 cells were exposed to a variety of reagents including hemin, rapamycin, imatinib, and/or decitabine (known erythroid inducers), and cultured in basic culture media or erythropoietin-based differentiation media...
March 7, 2018: Experimental Hematology
Renu Yadav, Nisha, Surajit Sarkar
Hemoglobins (Hbs) are evolutionarily conserved small globular proteins with characteristic 3-over-3 α-helical sandwich structure that is typically known as "globin fold". Hbs have been found to be involved in diverse biological functions and the characteristic property of oxygen transportation is relatively a recent adaptation. Drosophila genome possesses three globin genes (glob1, glob2, and glob3) and it was previously reported that adequate expression of glob1 is required for various aspects of development, and also to regulate the cellular level of reactive oxygen species (ROS)...
March 7, 2018: Experimental Cell Research
Christine C Helms, Mark T Gladwin, Daniel B Kim-Shapiro
Erythrocytes regulate vascular function through the modulation of oxygen delivery and the scavenging and generation of nitric oxide (NO). First, hemoglobin inside the red blood cell binds oxygen in the lungs and delivers it to tissues throughout the body in an allosterically regulated process, modulated by oxygen, carbon dioxide and proton concentrations. The vasculature responds to low oxygen tensions through vasodilation, further recruiting blood flow and oxygen carrying erythrocytes. Research has shown multiple mechanisms are at play in this classical hypoxic vasodilatory response, with a potential role of red cell derived vasodilatory molecules, such as nitrite derived nitric oxide and red blood cell ATP, considered in the last 20 years...
2018: Frontiers in Physiology
Chiara Antoniani, Vasco Meneghini, Annalisa Lattanzi, Tristan Felix, Oriana Romano, Elisa Magrin, Leslie Weber, Giulia Pavani, Sara El Hoss, Ryo Kurita, Yukio Nakamura, Thomas J Cradick, Ante S Lundberg, Matthew Porteus, Mario Amendola, Wassim El Nemer, Marina Cavazzana, Fulvio Mavilio, Annarita Miccio
Naturally occurring, large deletions in the β-globin locus result in hereditary persistence of fetal hemoglobin, a condition that mitigates the clinical severity of sickle-cell disease (SCD) and β-thalassemia. We designed a CRISPR/Cas9 strategy to disrupt a 13.6-kb genomic region encompassing the δ- and β-globin genes and a putative γ-δ intergenic fetal hemoglobin (HbF) silencer. Disruption of just the putative HbF silencer results in a mild increase in γ-globin expression, whereas deletion or inversion of a 13...
March 8, 2018: Blood
W X Li, Q W Ma, F Y Zeng
Objective: To study the function of ten-eleven translocation 2 (Tet2) in γ globin gene expression in patients with β- thalassemia. Methods: Gamma globin expression was induced by 5-azacytidine and Tet2 gene expression was knocked down by short hairpin RNA (shRNA) in a human immortalized myelogenous leukemia K562 cell line. The global 5-hydroxymethylcytosine (5hmC) level was measured by an ELISA kit. 5hmC level of γ globin gene was quantified by sulfite sequencing. The mRNA level of Tet2, γ globin, and related transcription factors Nfe4 and Klf1 were quantified by real-time PCR...
March 1, 2018: Zhonghua Nei Ke za Zhi [Chinese Journal of Internal Medicine]
Ferania Mella, Yasuhiro Yamashiro, Chris Adhiyanto, Tatehiko Tanaka, Takenori Nitta, Yuki Amao, Masafumi Kimoto
We report a new hemoglobin (Hb) variant, Hb Hachioji (HBB: c.187C>T), which was detected in a 32-year-old male with hemolytic anemia. The proband had undergone splenectomy in his childhood after being diagnosed with hereditary spherocytosis (HS) with no clinical improvement. A recent study showed that Heinz bodies were frequently observed in his red cells, however, no abnormal band was separated by isoelectric focusing (IEF), and the isopropanol (instability) test was negative. Direct sequencing revealed that the proband was a heterozygous carrier of a novel mutation (GCT>GTT) at codon 62 of the β-globin gene, leading to an alanine to valine substitution...
March 7, 2018: Hemoglobin
Jing Chen-Roetling, Sheng-Kai Ma, Yang Cao, Aishwarya Shah, Raymond F Regan
Hemopexin (Hpx) binds heme with extraordinary affinity, and after haptoglobin may provide a second line of defense against the toxicity of extracellular hemoglobin (Hb). In this series of experiments, the hypothesis that Hpx protects neurons from Hb neurotoxicity was evaluated in murine primary cultures containing neurons and glial cells. Contrary to hypothesis, Hpx increased neuronal loss due to micromolar concentrations of Hb by 4-12-fold, as measured by LDH release assay; conversely, the neurotoxicity of hemin was completely prevented...
March 3, 2018: Journal of Neurochemistry
Chen Sun, Chang Lu
Detecting three-dimensional (3D) genome organization in the form of physical interactions between various genomic loci is of great importance for understanding transcriptional regulations and cellular fate. Chromosome Conformation Capture (3C) method is the gold standard for examining chromatin organization, but usually requires a large number of cells (>107 ). This hinders studies of scarce tissue samples from animals and patients using the method. Here we developed a microfluidics-based approach for examining chromosome conformation by 3C technology...
March 2, 2018: Analytical Chemistry
Paul J Schmidt, Kaifeng Liu, Gary Visner, Kevin Fitzgerald, Shannon Fishman, Tim Racie, Julia L Hettinger, James S Butler, Mark D Fleming
Diminished β-globin synthesis in β-thalassemia is associated with ineffective erythropoiesis, leading to secondary iron overload caused by inappropriately low levels of hepcidin and to splenomegaly in the symptomatic thalassemias. Splenectomy is often employed in patients with β-thalassemia in order to reduce hemolysis. Expression of the iron regulatory peptide hormone hepcidin is repressed by the serine protease TMPRSS6. Hepcidin induction by RNAi-mediated inhibition of TMPRSS6 expression reduces iron overload and mitigates anemia in murine models of β-thalassemia intermedia...
March 2, 2018: American Journal of Hematology
Sheng He, Jihui Li, Peng Huang, Shujie Zhang, Li Lin, Yangjin Zuo, Xiaoxian Tian, Chenguang Zheng, Xiaoxia Qiu, Biyan Chen
Hb Bart's hydrops fetalis is the most severe and generally fatal clinical phenotype of α-thalassemia (α-thal), which is due to the deletion of all four functional α-globin genes of hemoglobin (Hb), resulting in no α-globin chain production (- -/- -). Homozygosity for the - -SEA (Southeast Asian) α-globin gene deletion is the main cause of the Hb Bart's hydrops fetalis in Asia, especially South China. Occasionally, other α0 -thal deletions can also be found. In this study, we report a case with an atypical form of Hb Bart's hydrops fetalis that was caused by - -SEA and a large novel α0 -thal deletion (- -GX ) (Guangxi)...
March 1, 2018: Hemoglobin
Sitthichai Panyasai, Surada Satthakarn, Sakorn Pornprasert
Hb Q-Thailand [α74(EF3)Asp→His (α1), GAC>CAC, HBA1: c.223G>C] is an abnormal hemoglobin (Hb) frequently found in Thailand and Southeast Asian countries. The association of the αQ-Thailand allele with other globin gene disorders has important implications in diagnosis. Here, we report how to diagnose the coinheritance of Hb Q-Thailand with β-thalassemia (β-thal)/Hb E disease in four Thai samples from high performance liquid chromatography (HPLC) and capillary electrophoresis (CE) testing results...
February 27, 2018: Hemoglobin
Attawut Chaibunruang, Kritsada Singha, Hataichanok Srivorakun, Goonnapa Fucharoen, Supan Fucharoen
Hb New York or Hb Kaohsiung [β113(G15)Val→Glu (GTG>GAG), HBB: c.341T>A] has been considered a rare β hemoglobin (Hb) variant found originally in an Iranian woman and later in diverse populations but its genetic origin has not been elucidated. Here we report molecular and hematological descriptions of this variant found in the Thai population. Among 5643 subjects referred for hemoglobinopathy investigation during January 2015 to September 2017, 183 (3.2%) were found to carry several Hb variants, including β chain variants (n = 135, 2...
February 21, 2018: Hemoglobin
Amaliris Guerra, Khaled M Musallam, Ali T Taher, Stefano Rivella
At present, the only definitive cure for β-thalassemia is a bone marrow transplant (BMT); however, HLA-blood-matched donors are scarcely available. Current therapies undergoing clinical investigation with most potential for therapeutic benefit are the β-globin gene transfer of patient-specific hematopoietic stem cells followed by autologous BMT. Other emerging therapies deliver exogenous regulators of several key modulators of erythropoiesis or iron homeostasis. This review focuses on current approaches for the treatment of hemoglobinopathies caused by disruptions of β-globin...
April 2018: Hematology/oncology Clinics of North America
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