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Alison T Merryweather-Clarke, Alex J Tipping, Abigail A Lamikanra, Rui Fa, Basel Abu-Jamous, Hoi Pat Tsang, Lee Carpenter, Kathryn J H Robson, Asoke K Nandi, David J Roberts
BACKGROUND: Human-induced pluripotent stem cells (hiPSCs) are a potentially invaluable resource for regenerative medicine, including the in vitro manufacture of blood products. HiPSC-derived red blood cells are an attractive therapeutic option in hematology, yet exhibit unexplained proliferation and enucleation defects that presently preclude such applications. We hypothesised that substantial differential regulation of gene expression during erythroid development accounts for these important differences between hiPSC-derived cells and those from adult or cord-blood progenitors...
October 21, 2016: BMC Genomics
Supawadee Yamsri, Naruwat Pakdee, Goonnapa Fucharoen, Kanokwan Sanchaisuriya, Supan Fucharoen
Non-transfusion-dependent thalassemia (NTDT) is associated with various forms of thalassemia and genetic modifiers. We report the molecular basis of NTDT in hemoglobin (Hb) E-β-thalassemia disease. This study was done in 73 adult patients encountered at the prenatal diagnosis center of Khon Kaen University, Northeast Thailand. Hematological parameters and Hb patterns were collected, and α- and β-globin gene mutations were determined. Multiple single-nucleotide polymorphisms (SNPs) including the rs7482144/Gγ-XmnI polymorphism, rs2297339, rs2838513, rs4895441, and rs9399137 in the HBS1L-MYB gene, rs4671393 and rs11886868 in the BCL11A gene, and G176AfsX179 in the KLF1 gene were examined...
October 7, 2016: Acta Haematologica
Elenoe C Smith, Sidinh Luc, Donyell M Croney, Mollie B Woodworth, Luciano C Greig, Yuko Fujiwara, Minh Nguyen, Falak Sher, Jeffrey D Macklis, Daniel E Bauer, Stuart H Orkin
BCL11A, a repressor of human fetal (γ-)globin expression, is required for immune and hematopoietic stem cell functions and brain development. Regulatory sequences within the gene, which are subject to genetic variation affecting fetal globin expression, display hallmarks of an erythroid enhancer in cell lines and transgenic mice. As such this enhancer is a novel, attractive target for therapeutic gene editing. To explore the roles of such sequences in vivo, we generated mice in which the orthologous 10 kb intronic sequences were removed...
October 5, 2016: Blood
Nelson C N Chan, Kin-Mang Lau, Kelvin C K Cheng, Natalie P H Chan, Margaret H L Ng
Genetic association studies showed that Hb F is under the influence of major quantitative trait loci (QTL) in β-thalassemia (β-thal) carriers. Single nucleotide polymorphisms (SNPs) at three major QTLs, BCL11A, HBS1L-MYB intergenic region and XmnI-HBG2, were individually validated in univariate models. However, their relative effect sizes on Hb F regulation are unknown. We genotyped 99 Chinese β-thal carriers for the three major QTLs and performed genetic association studies using three different statistical models, including mass univariate analysis, multivariate linear regression and partial least square regression structural equation modeling (PLS-SEM)...
October 5, 2016: Hemoglobin
Hani Bagheri, Chansonette Badduke, Ying Qiao, Rita Colnaghi, Iga Abramowicz, Diana Alcantara, Christopher Dunham, Jiadi Wen, Robert S Wildin, Malgorzata J M Nowaczyk, Jennifer Eichmeyer, Anna Lehman, Bruno Maranda, Sally Martell, Xianghong Shan, Suzanne M E Lewis, Mark O'Driscoll, Cheryl Y Gregory-Evans, Evica Rajcan-Separovic
The 2p15p16.1 microdeletion syndrome has a core phenotype consisting of intellectual disability, microcephaly, hypotonia, delayed growth, common craniofacial features, and digital anomalies. So far, more than 20 cases of 2p15p16.1 microdeletion syndrome have been reported in the literature; however, the size of the deletions and their breakpoints vary, making it difficult to identify the candidate genes. Recent reports pointed to 4 genes (XPO1, USP34, BCL11A, and REL) that were included, alone or in combination, in the smallest deletions causing the syndrome...
March 17, 2016: JCI Insight
Laleh Shariati, Hossein Khanahmad, Mansoor Salehi, Zahra Hejazi, Ilnaz Rahimmaesh, Mohammad Amin Tabatabaiefar, Mohammad Hossein Modarressi
BACKGROUND: β-thalassemia is a major group of human genetic disorders which involves decrease or cease in the normal synthesis of the β-globin chains of hemoglobin. KLF1 is a key regulatory molecule involved in the γ to β-globin gene switching process directly inducing the expression of beta globin gene and indirectly repressing gamma globin. This study was performed to investigate the ability of an engineered CRISPR/Cas9 system to disrupt the KLF1 gene to inhibit the γ to β hemoglobin switching process in K562 cells...
September 26, 2016: Journal of Gene Medicine
Santosh L Saraf, Binal N Shah, Xu Zhang, Jin Han, Bamidele O Tayo, Taimur Abbasi, Adam Ostrower, Elizabeth Guzman, Robert E Molokie, Michel Gowhari, Johara Hassan, Shivi Jain, Richard S Cooper, Roberto F Machado, James P Lash, Victor R Gordeuk
No abstract text is available yet for this article.
September 22, 2016: Haematologica
Khuthala Mnika, Gift D Pule, Collet Dandara, Ambroise Wonkam
Sickle cell disease (SCD) is a blood disease caused by a single nucleotide substitution (T > A) in the beta globin gene on chromosome 11. The single point mutation (Glu6Val) promotes polymerization of hemoglobin S (HbS) and causes sickling of erythrocytes. Vaso-occlusive painful crises are associated with recurrent and long-term use of analgesics/opioids and hydroxyurea (HU) by people living with SCD. The present analysis offers a state-of-the-art expert review of the effectiveness of pharmacogenomics/genetics of pain management in SCD, with specific focus on HU and opioids...
October 2016: Omics: a Journal of Integrative Biology
Christian Brendel, Swaroopa Guda, Raffaele Renella, Daniel E Bauer, Matthew C Canver, Young-Jo Kim, Matthew M Heeney, Denise Klatt, Jonathan Fogel, Michael D Milsom, Stuart H Orkin, Richard I Gregory, David A Williams
Reducing expression of the fetal hemoglobin (HbF) repressor BCL11A leads to a simultaneous increase in γ-globin expression and reduction in β-globin expression. Thus, there is interest in targeting BCL11A as a treatment for β-hemoglobinopathies, including sickle cell disease (SCD) and β-thalassemia. Here, we found that using optimized shRNAs embedded within an miRNA (shRNAmiR) architecture to achieve ubiquitous knockdown of BCL11A profoundly impaired long-term engraftment of both human and mouse hematopoietic stem cells (HSCs) despite a reduction in nonspecific cellular toxicities...
October 3, 2016: Journal of Clinical Investigation
Thais A Fornari, Carolina Lanaro, Dulcinéia M Albuquerque, Regiane Ferreira, Fernando F Costa
Hereditary persistence of fetal hemoglobin deletion type-2 (HPFH-2) and Sicilian-δβ-thalassemia are conditions described as large deletions of the human β-like globin cluster, with absent β-globin chains and a compensatory variable increase in γ-globin. HPFH, in general, may be distinguished from DB-Thalassemia by higher fetal hemoglobin (HbF) levels, absence of anemia and hypochromic and microcytic erythrocytes. MicroRNAs (miRNAs) regulate a range of cellular processes including erythropoiesis and regulation of transcription factors such as the BCL11A and SOX6 genes, which are related to the regulation of γ-globin expression...
September 3, 2016: Experimental Biology and Medicine
Xiang Zhang, Lijuan Wang, Yingmei Wang, Shenjia Shi, Huayu Zhu, Fengjin Xiao, Jing Yang, Angang Yang, Xiaoke Hao
Forkhead box Q1 (FOXQ1) has been recognized as an oncogene that is overexpressed in different cancers, and several studies have shown that FOXQ1 is related to apoptosis and proliferation in many cancer types. However, the role and the molecular mechanism of FOXQ1 in prostate cancer remains unclear. In this study, we aimed to explore the role of FOXQ1 in regulating cell apoptosis, proliferation and invasion in prostate cancer and the underlying mechanism. We found that FOXQ1 was highly expressed in the prostate cancer tissues and cell lines...
October 2016: Oncology Reports
Vinod Vathipadiekal, John J Farrell, Shuai Wang, Heather L Edward, Heather Shappell, A M Al-Rubaish, Fahad Al-Muhanna, Z Naserullah, A Alsuliman, Hatem Othman Qutub, Irene Simkin, Lindsay A Farrer, Zhihua Jiang, Hong-Yuan Luo, Shengwen Huang, Gustavo Mostoslavsky, George J Murphy, Pradeep K Patra, David H K Chui, Abdulrahman Alsultan, Amein K Al-Ali, Paola Sebastiani, Martin H Steinberg
Fetal hemoglobin (HbF) levels are higher in the Arab-Indian (AI) β-globin gene haplotype of sickle cell anemia compared with African-origin haplotypes. To study genetic elements that effect HbF expression in the AI haplotype we completed whole genome sequencing in 14 Saudi AI haplotype sickle hemoglobin homozygotes-seven selected for low HbF (8.2% ± 1.3%) and seven selected for high HbF (23.5% ± 2.6%). An intronic single nucleotide polymorphism (SNP) in ANTXR1, an anthrax toxin receptor (chromosome 2p13), was associated with HbF...
August 7, 2016: American Journal of Hematology
Cristina Dias, Sara B Estruch, Sarah A Graham, Jeremy McRae, Stephen J Sawiak, Jane A Hurst, Shelagh K Joss, Susan E Holder, Jenny E V Morton, Claire Turner, Julien Thevenon, Kelly Mellul, Gabriela Sánchez-Andrade, Ximena Ibarra-Soria, Pelagia Deriziotis, Rui F Santos, Song-Choon Lee, Laurence Faivre, Tjitske Kleefstra, Pentao Liu, Mathew E Hurles, Simon E Fisher, Darren W Logan
Intellectual disability (ID) is a common condition with considerable genetic heterogeneity. Next-generation sequencing of large cohorts has identified an increasing number of genes implicated in ID, but their roles in neurodevelopment remain largely unexplored. Here we report an ID syndrome caused by de novo heterozygous missense, nonsense, and frameshift mutations in BCL11A, encoding a transcription factor that is a putative member of the BAF swi/snf chromatin-remodeling complex. Using a comprehensive integrated approach to ID disease modeling, involving human cellular analyses coupled to mouse behavioral, neuroanatomical, and molecular phenotyping, we provide multiple lines of functional evidence for phenotypic effects...
August 4, 2016: American Journal of Human Genetics
Sneha Dadheech, D Madhulatha, Suman Jainc, James Joseph, A Jyothy, Anjana Munshi
BACKGROUND & OBJECTIVES: The amount of foetal haemoglobin that persists in adulthood affects the clinical severity of haemoglobinopathies including β-thalassaemia major and sickle cell anaemia (SCA). The present study was undertaken to analyse β-thalassaemia as well as SCA patients for the single nucleotide polymorphism (SNP), rs11886868 (T/C) in BCL11A gene and to evaluate the association between this polymorphism and severity of β-thalassaemia major and SCA. METHODS: a total of 620 samples (420 β-thalassaemia major and 200 SCA cases) were analysed before blood transfusion using basic screening tests like complete blood analysis and osmotic fragility and further confirmed by high performance liquid chromatography (HPLC), amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) and reverse dot blot techniques...
April 2016: Indian Journal of Medical Research
Elenoe C Smith, Stuart H Orkin
The β-hemoglobinopathies are inherited disorders resulting from altered coding potential or expression of the adult β-globin gene. Impaired expression of β-globin reduces adult hemoglobin (HbA, α2β2) production, the hallmark of β-thalassemia. A single base mutation at codon 6 leads to formation of HbS (α2β(S) 2) and sickle cell disease. While the basis of these diseases is known, therapy remains largely supportive. Bone marrow transplantation is the only curative therapy. Patients with elevated levels of fetal hemoglobin (HbF, α2γ2) as adults exhibit reduced symptoms and enhanced survival...
June 23, 2016: Human Molecular Genetics
Philipp M Altrock, Christian Brendel, Raffaele Renella, Stuart H Orkin, David A Williams, Franziska Michor
Recent advances in gene therapy and genome-engineering technologies offer the opportunity to correct sickle cell disease (SCD), a heritable disorder caused by a point mutation in the β-globin gene. The developmental switch from fetal γ-globin to adult β-globin is governed in part by the transcription factor (TF) BCL11A. This TF has been proposed as a therapeutic target for reactivation of γ-globin and concomitant reduction of β-sickle globin. In this and other approaches, genetic alteration of a portion of the hematopoietic stem cell (HSC) compartment leads to a mixture of sickling and corrected red blood cells (RBCs) in periphery...
September 2016: American Journal of Hematology
Jiawei Yin, Fan Zhang, Huiquan Tao, Xiao Ma, Guangsong Su, Xiaoli Xie, Zhongjuan Xu, Yanwen Zheng, Hong Liu, Chao He, Zhengwei Jenny Mao, Zhiwei Wang, Weirong Chang, Robert Peter Gale, Depei Wu, Bin Yin
Chronic myeloid leukemia (CML) has chronic and acute phases. In chronic phase myeloid differentiation is preserved whereas in acute phase myeloid differentiation is blocked. Acute phase CML resembles acute myeloid leukemia (AML). Chronic phase CML is caused by BCR-ABL1. What additional mutation(s) cause transition to acute phase is unknown and may differ in different persons with CML. BCL11A encodes a transcription factor and is aberrantly-expressed in several haematological and solid neoplasms. We analyzed BCL11A mRNA levels in subjects with chronic and acute phase CML...
August 2016: Leukemia Research
Wanicha Tepakhan, Supawadee Yamsri, Kanokwan Sanchaisuriya, Goonnapa Fucharoen, Xiangmin Xu, Supan Fucharoen
Hemoglobin E is the most common Hb variant found in South East Asia. Variation of Hb F expression in Hb E syndrome is associated with several genetic modifiers. We report several single nucleotide polymorphisms (SNPs), including nine known and five novel mutations of the Krüppel-like factor 1 (KLF1; an erythroid specific transcription factor) gene and determine their associations with phenotypic expression of Hb F in Hb E disorders. KLF1 mutations were examined using high resolution melting (HRM) assay and DNA sequencing in 575 homozygous Hb E, 278 heterozygous Hb E and 100 normal subjects...
July 2016: Blood Cells, Molecules & Diseases
Raphaël Mourad, Olivier Cuvier
Recent advances in long-range Hi-C contact mapping have revealed the importance of the 3D structure of chromosomes in gene expression. A current challenge is to identify the key molecular drivers of this 3D structure. Several genomic features, such as architectural proteins and functional elements, were shown to be enriched at topological domain borders using classical enrichment tests. Here we propose multiple logistic regression to identify those genomic features that positively or negatively influence domain border establishment or maintenance...
May 2016: PLoS Computational Biology
Beate Peter, Ellen M Wijsman, Alejandro Q Nato, Mark M Matsushita, Kathy L Chapman, Ian B Stanaway, John Wolff, Kaori Oda, Virginia B Gabo, Wendy H Raskind
Childhood apraxia of speech (CAS) is a severe and socially debilitating form of speech sound disorder with suspected genetic involvement, but the genetic etiology is not yet well understood. Very few known or putative causal genes have been identified to date, e.g., FOXP2 and BCL11A. Building a knowledge base of the genetic etiology of CAS will make it possible to identify infants at genetic risk and motivate the development of effective very early intervention programs. We investigated the genetic etiology of CAS in two large multigenerational families with familial CAS...
2016: PloS One
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