scholarly journals Ultimos avances en el tratamiento de la enfermedad de células falciformes.

2013 ◽  
Vol 5 (4) ◽  
Author(s):  
María del Pilar AGUINAGA ◽  
Ernest Alvin TURNER
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Genetic Disorders ◽  
Globin Gene ◽  
Cell Disease ◽  
Homozygous State ◽  
Clinical Complications ◽  
New Treatments ◽  
Number Of Individuals

Sickle cell disease is define as a group of genetic disorders characterized by the presence of hemoglobin S, anemia, and acute and chronic tissue damage. Sickle cell anemia is the most common type of sickle cell disease, and is caused by the presence of the βs- globin gene in the homozygous state. At present there is no cure for sickle cell anemia except for bone marrow transplantantion, which is available only to a limited number of individuals. The lack of drugs or treatments to cure sickle cell disease is due in part to the absence of good experimental animal models. The recently available sickle cell transgenic mice models should promote the experimentation of new treatments for sickle cell disease. Until a cure is found, the treatment would continue to alleviate the clinical complications associated with the disease. Un update on immunizations, prophylactic penicillin, folic acid, trental, chelation and iron therapy, experimental and other drugs for treatment of sickle cell anemia is presented in this article.

Clinical Complications in Adult Patients with Sickle Cell Anemia and β-Thalassemia-Sickle Cell Disease

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4767-4767
Author(s):  
Giovanna Graziadei ◽  
Alessia Marcon ◽  
Martina Soldarini ◽  
Ilaria Gandolfi ◽  
Luisa Ronzoni ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Acute Chest Syndrome ◽  
P Value ◽  
Cell Disease ◽  
Transfusion Therapy ◽  
Clinical Complications ◽  
Significant Difference ◽  
The Mean

Abstract Abstract 4767 Background. Sickle-Cell Disease (SCD) is one of the most common severe monogenic inherited disorders worldwide, due to hemoglobin S (HbS), with reduced affinity for the oxygen. HbS polymerization, leading to erythrocyte rigidity, vaso-occlusion and hemolytic anemia, is central in the pathophysiology and crucial for the clinical outcome. The term SCD refers to Sickle Cell Anemia (SCA) due to homozygosis for βS allele, HbS/β-thalassemia (T-SCD) due to compound of β-thal and βS allele, and HbSC disease, owing to the coinheritance of βS and βcalleles. SCD is a multiorgan disease characterized by recurrent acute events and progressive organ damage, worsening during the life. Aims. This is a retrospective monocentric study aimed to assess and compare the clinical complications among 59 adult SCD patients, followed at the Hereditary Anemia Centre of the Foundation IRCCS “Ca Granda” Ospedale Maggiore Policlinico, in Milan, Italy. Methods. Mutation analysis of the b globin gene was established by direct DNA sequencing on the ABI Prism 310 genetic analyzer. Clinical and hematological features were evaluated by routine tests and physical examination, with special attention to the erythropoiesis stress parameters as LDH values and extramedullary erythropoietic (EE) masses. Results. Fifty-nine adult SCD patients, 16 SCA and 43 T-SCD, were evaluated. In T-SCD patients detected b-mutations were severe (b°) in 69.8%, and moderate or mild (b+-b++) in 30.2%. The mean age of SCA patients was 36±9 and 41±11 years for T-SCD patients. For both groups the mean follow-up was 20±6 years, while the mean age at the presentation in our Centre was 32±8 years in SCA patients and 31±10 years in T-SCD ones. Five out of 16 (31.2%) SCA patients and 16/43 (37.2%) T-SCD patients were male. HbF mean levels were 6.9±5.1% and 10.1±7.2%, respectively in SCA and T-SCD group; surprisingly Hb mean levels were lower in SCA (9.3±1.3 g/dl) than in T-SCD (9.9±1.4 g/dl) patients. Comparing SCA and T-SCD, there was statistically significant difference in splenic features: splenectomy was performed in 2/16 (12.5%) SCA patients vs 21/43 (48.8%) T-SCD patients (p-value < 0.01). Splenomegaly was absent in SCA, while was detected in 11/22 (50%) T-SCD (p-value < 0.0001); all SCA patients had functional asplenia, not observed in T-SCD patients; splenic infarctions were absent in SCA patients and were detected in 7/22 (31.8%) T-SCD patients, of whom 5 had splenomegaly and 2 had normal spleen size (pvalue <0.001). On the other side, there was not statistically significant difference in the prevalence of stroke, acute chest syndrome (ACS), bone pain crisis, sepsis, leg ulcers and priapism. However, we observed some clinical differences, even if not statistically significant. Cholecistectomy was performed in 4/16 (25%) SCA patients vs 17/43 (39.5%) T-SCD patients, and gallstones were detected respectively in 5/12 (41.7%) and in 14/26 (53.8%) of SCA and T-SCD patients. Thrombotic events were absent in SCA patients, compared to 4/43 (9.3%) T-SCD patients. Furthermore, we detected EE in 3/16 (18.6%) SCA and in 3/43 (7%) T-SCD, all carrying b° thal mutations. We underlie that Hb levels and LDH values were higher in SCA than in T-SCD patients (823±295 vs 689±209 U/L). About the treatment, 14/16 (87.5%) SCA and 31/43 (72%) T-SCD underwent to top-up transfusion; 5/43 (11.6%) T-SCD were regularly transfused. Seven out of 16 (43.8%) SCA and 18/43 (41.8%) T-SCD patients were treated with Hydroxycarbamide (HU). Criteria for transfusion therapy were: painful crisis not responsive to HU, major clinical complications, such as stroke or ACS, extramedullary erythropoietic masses associated with high LDH levels and low Hb values. Conclusions. These data suggest that SCA and T-SCD patients have similar clinical course. Splenomegaly is present only in T-SCD patients, probably due to the increased amount of extravascular hemolysis. Surprisingly, SCA patients showed EE and lower Hb levels with higher LDH values compared to T-SCD ones. This could be related to the prevalence of intravascular hemolysis, that can lead to erythropoietic stress in SCA, even if tissues are better oxygenated in these patients because of biochemical characteristic of HbS in terms of decreased oxygen affinity. These observations could be important to evaluate transfusion and HU treatment. Disclosures: Cappellini: Novartis: Research Funding.

scholarly journals Analysis of hemoglobin F production in Saudi Arabian families with sickle cell anemia

Blood ◽  
1987 ◽  
Vol 70 (3) ◽  
pp. 716-720 ◽  
Author(s):  
BA Miller ◽  
M Salameh ◽  
M Ahmed ◽  
N Olivieri ◽  
G Antognetti ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Cell Disease ◽  
Erythroid Progenitors ◽  
Hemoglobin F ◽  
Gamma Globin ◽  
Hemoglobin Production

Erythrocytes and progenitor-derived erythroblasts of sickle cell anemia patients from the Eastern Province of Saudi Arabia contain increased fetal hemoglobin and G gamma globin. A distinctive DNA polymorphism haplotype in the beta globin gene cluster (++- +-), tightly coupled to a C----T substitution at position -158 5′ to the cap site of the G gamma globin gene, is strongly associated with sickle cell disease in this region. To determine whether the increased fetal hemoglobin production and/or elevated G gamma globin content are tightly linked to this haplotype, we studied 55 members of five Saudi families in which sickle cell disease is present. The results did not suggest a tight linkage of the haplotype to increased fetal hemoglobin production. On the other hand, several sickle trait family members heterozygous for the haplotype had normal fetal hemoglobin production in culture but elevated G gamma to A gamma ratios in peripheral blood. This observation suggests that in this genetic background increased expression of the G gamma globin gene may occur without a measurable increase in total fetal hemoglobin production. The family studies also clearly demonstrate that increased fetal hemoglobin production by erythroid progenitors is dependent on zygosity for the sickle gene in this population. These findings strongly suggest that other factors, such as the products of genes stimulated by hemolytic stress or other genetic determinants associated with the Saudi beta S chromosome, may interact with the -158 C----T substitution and influence gamma globin gene expression in this population.

Association of Polymorphisms of the Transforming Growth Factor-β/Bone Morphogenetic Protein (TGF-β/BMP) Pathway with Sickle Cell Bacteremia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3170-3170
Author(s):  
Adeboye H. Adewoye ◽  
Vikki G. Nolan ◽  
Clinton T. Baldwin ◽  
Diego F. Wyszynski ◽  
Qian-Li Ma ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Candidate Genes ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Leukocyte Count ◽  
Globin Gene ◽  
Second Phase ◽  
Cell Disease ◽  
P Values ◽  
Bmp Pathway

Abstract Patients with sickle cell disease have an increased risk of bacteremia. To study the genetic basis for this increased susceptibility we studied the association of single nucleotide polymorphisms (SNPs) in candidate genes that might affect the risk of infection and therefore bacteremia. The Cooperative Study of Sickle Cell Disease enrolled 4,082 patients who were observed for about 5 years. Blood from these patients was used for globin gene analysis and SNP genotyping. We limited the present studies to patients with sickle cell anemia, with or without coincident α thalassemia, yielding a pool of 1473 patients with genotype, demographic and clinical data for which DNA samples were available. A case was defined as a patient seen in a clinic, emergency department, or hospital for which a positive blood culture not associated with a known source of infection such as osteomyelitis, septic arthritis, pneumonia, or meningitis, was found. Control patients had no history of bacteremia and no incident bacteremic events. For genetic studies, the samples were genotyped for informative SNPs in candidate genes selected from public and proprietary databases using the Sequenom mass spectrometry SNP genotyping system. For quality control purposes about 3% of the DNA samples were regenotyped and Hardy-Weinberg equilibrium was assessed for each SNP among controls. Genotypic counts were compared between sickle cell patients with bacteremia and patients using multiple logistic regression adjusting for leukocyte count, penicillin prophylaxis, fetal hemoglobin and total hemoglobin levels. In our initial screen, we considered a SNP to have an association with a phenotype when the p-value was equal to or less than 0.01, or if this and other SNPs in the same gene were significant at the 0.05 level. If a SNP met these criteria, a second phase of genotyping was done to study additional haplotype tagging (ht) SNPs in the gene. Because of the importance of the TGF-β beta pathway in the immune response, additional genes in this pathway were also studied. The ABI SNPlex system was utilized for the second phase of genotyping. Among the 201 subjects with bacteremia and 1238 controls, there was no significant difference in age, sex, HbF concentration, distribution of β-globin gene cluster haplotypes or the presence of coincident α thalassemia. Patients with bacteremia had a slightly lower hemoglobin concentration and higher leukocyte count. Subjects who received antibiotic prophylaxis (p &lt; 0.0001) or H. influenza vaccination (p &lt;0.004) were more likely to develop bacteremia, but with a ‘non-covered’ organism. Four SNPs in BMP6 (rs270387, rs267188, rs267196 and rs366386; p values &lt; 0.039), 2 SNPs in TGFBR3 (rs2148322 and rs2765888; p values &lt; 0.033) and 2 SNPs in SMAD3 (rs10518707 and rs11631380; p values &lt; 0.012) were associated with bacteremia. The TGF-β/BMP pathway modulates immunosuppression, cell migration, wound healing and angiogenesis, among other functions. In some studies, reduced levels of these proteins were associated with increased severity of bacterial pneumonia. SNPs that show an association with susceptibility to bacteremia may help target sickle cell anemia patients who require more prolonged antibiotic prophylaxsis.

High Oxygen Environment during Pregnancy Rescues Sickle Cell Animia Mouse from Prenatal Death.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1594-1594
Author(s):  
Lin Ye ◽  
Judy C. Chang ◽  
Kalee Chan ◽  
Ronghua Lu ◽  
Yuet Wai Kan
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Globin Gene ◽  
Pathological Finding ◽  
High Oxygen ◽  
Intrauterine Death ◽  
Globin Genes ◽  
Cell Disease ◽  
Oxygen Environment

Abstract Several mouse models for sickle cell disease have been developed for the studies of the pathophysiology of sickle cell disease and the investigations of drug and gene therapies. In previous years, we have also succeeded in producing a sickle cell anemia mouse model. In this model the endogenous mouse α and β globin genes were knocked out and replaced by the human α and βs globin transgenes. The βs globin gene is contained in a 240kb YAC that preserves the entire native genomic context of the β-globin locus. These mice have anemia, reticulocytosis and irreversible sickle cells in the peripheral blood, as well as other pathological features of sickle cell disease. However, their γ globin switches to βs globin expression from around 12 days of gestation. The low level of fetal hemoglobin expression in utero led to intrauterine sickling and fetal death so that very few live-born sickle cell anemia mice could be obtained. To rescue these mice from intrauterine death we investigated the effect of placing the pregnant mothers into a high O2 environment. From the tenth day of gestation onwards, we placed the mothers into a chamber containing 50% O2 and kept the newborn pups in it for another 10 days after birth. The frequency of sickle cell anemia mice we obtained was increased from 0.2% to 32%. Moreover, 55% to 88% of the newborn sickle cell anemia mice survived in the oxygen treated group, whereas none of the sickle cell anemia mice survived in regular air breeding conditions. The survived sickle cell anemia mice develop congestion, atrophy, and infarcts in multiple organs by histological analysis. These pathological finding are very similar to those find in patients with sickle cell disease. We conclude that a high oxygen environment can be used to obtain more sickle cell anemia mice in those models that have a high perinatal mortality. The higher yield of these mice will facilitate physiological and therapeutic studies of sickle cell anemia.

Fetal Hemoglobin In Sickle Cell Anemia: A Glass Half Full?

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4691-4691
Author(s):  
Martin H. Steinberg ◽  
David H.K. Chui ◽  
George J. Dover ◽  
Paola Sebastiani ◽  
Abdulrahman Alsultan
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Conflicts Of Interest ◽  
Globin Gene ◽  
Single Agent ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Sickle Erythrocytes ◽  
F Cells

HbF modulates the phenotype of sickle cell anemia by inhibiting deoxyHbS polymerization. HbF is confined to erythrocytes called F-cells that can be detected by FACS when these cells contain sufficient HbF. Measuring the amount of HbF/F-cell is difficult and not clinically available. African-Americans with sickle cell anemia have 2-80% F-cells with an average HbF/F-cell of 6.4±1.6 pg. The distribution of HbF/F-cell is highly individual regardless of HbF level. People with HbS-gene deletion hereditary persistence of HbF (HPFH) have a mean HbF of 30%, and HbF is evenly distributed among their erythrocytes. Polymer is not present in these cells either experimentally or after calculating the HbS polymer fraction at 70% O2 saturation. Therefore, each cell contains about 10 pg. of HbF. DeoxyHbS polymerization is prevented at physiologic venous and capillary O2 saturations of 40-70% when HbF/F-cell is 9-12 pgs. We call this the “protective” level of HbF. F-cells need not contain “protective” levels of HbF. Some β-globin gene cluster haplotypes are associated with high HbF. Carriers of these haplotypes can have milder disease. Nevertheless, even patients with high HbF can have frequent painful episodes, acute chest syndrome and osteonecrosis. Patients with HbS-δβ thalassemia have 15 to 25% HbF but are anemic and have vasoocclusive complications, albeit less often than in sickle cell anemia. Hydroxyurea reduces the morbidity and mortality of sickle cell anemia, an effect likely to be mediated by its induction of HbF. Patients treated with hydroxyurea are better and probably live longer, but adults are anemic and rarely asymptomatic. In all these patient groups, HbF is unevenly distributed among erythrocytes. In contrast, people with HbS-HPFH are nearly asymptomatic and not anemic. The failure of HbF to modulate uniformly all complications of sickle cell disease might be related to the heterogeneous concentration of HbF in sickle erythrocytes. HbF is associated with protection from the development of certain disease subphenotypes but has limited prognostic value in individuals. In many cross-sectional studies, high HbF was associated with a reduced rate of acute painful episodes, fewer leg ulcers, less osteonecrosis, less frequent acute chest syndromes and reduced disease severity. HbF had a weak or no clear association with priapism, urine albumin excretion, stroke and silent cerebral infarction, systemic blood pressure and tricuspid regurgitant velocity. Perhaps this is because intravascular hemolysis of cells with little or no HbF causes nitric oxide scavenging, or because these complications are less dependent on HbS polymerization. No study provides information on the concentration of HbF/F-cell other than providing the relatively meaningless calculated mean value. Rather than the total number of F-cells or the concentration of HbF in the hemolysate, HbF/F-cell and the proportion of F-cells that have “protective” HbF is the most critical predictor of the likelihood of some disease subphenotypes. Hypothetical distributions of HbF-cells with different levels of HbF/F-cell can be plotted for different concentrations of HbF. With mean HbF levels of 5%, 10% and 20%, and HbF content per cell of 1.5, 3 and 6 pg., assuming a fixed mean, the variance was changed to show how the distribution of HbF per cell can greatly vary, even if the mean is constant. For example, with 20% HbF, as few as 1% and as many as 24% of cells have “protective” HbF. When HbF is lower, few or no “protected” cells can be present. Due to the heterogeneous concentrations of HbF, HbS can polymerize in some F-cells that have sub-polymer inhibiting concentrations of HbF. Inducing high levels of HbF is one approach to treating sickle cell disease. Inactivating BCL11A, a repressor of γ-globin gene expression, abrogates sickle cell disease in transgenic sickle mice. Their HbF was distributed homogeneously, and their phenotype mimicked HbS-HPFH. If it becomes possible in humans to target BCL11A or its pathway with agents that affect gene transcription, will it result in pancellular HbF? Broadening the distribution of HbF amongst sickle erythrocytes with drugs like hydroxyurea that effect the kinetics of erythropoiesis, coupled with an agent whose primary mechanism of action is to increase the transcription of the γ-globin genes, might be the most fruitful approach to HbF induction therapy and more efficacious than single agent treatment. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Analysis of hemoglobin F production in Saudi Arabian families with sickle cell anemia

Blood ◽  
1987 ◽  
Vol 70 (3) ◽  
pp. 716-720 ◽  
Author(s):  
BA Miller ◽  
M Salameh ◽  
M Ahmed ◽  
N Olivieri ◽  
G Antognetti ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Cell Disease ◽  
Erythroid Progenitors ◽  
Hemoglobin F ◽  
Gamma Globin ◽  
Hemoglobin Production

Abstract Erythrocytes and progenitor-derived erythroblasts of sickle cell anemia patients from the Eastern Province of Saudi Arabia contain increased fetal hemoglobin and G gamma globin. A distinctive DNA polymorphism haplotype in the beta globin gene cluster (++- +-), tightly coupled to a C----T substitution at position -158 5′ to the cap site of the G gamma globin gene, is strongly associated with sickle cell disease in this region. To determine whether the increased fetal hemoglobin production and/or elevated G gamma globin content are tightly linked to this haplotype, we studied 55 members of five Saudi families in which sickle cell disease is present. The results did not suggest a tight linkage of the haplotype to increased fetal hemoglobin production. On the other hand, several sickle trait family members heterozygous for the haplotype had normal fetal hemoglobin production in culture but elevated G gamma to A gamma ratios in peripheral blood. This observation suggests that in this genetic background increased expression of the G gamma globin gene may occur without a measurable increase in total fetal hemoglobin production. The family studies also clearly demonstrate that increased fetal hemoglobin production by erythroid progenitors is dependent on zygosity for the sickle gene in this population. These findings strongly suggest that other factors, such as the products of genes stimulated by hemolytic stress or other genetic determinants associated with the Saudi beta S chromosome, may interact with the -158 C----T substitution and influence gamma globin gene expression in this population.

scholarly journals CONTRIBUTION OF MARITAL DISTANCE TO COMMUNITY INBREEDING, HOMOZYGOSIS, AND REPRODUCTIVE WASTAGE FOR RECESSIVELY INHERITED GENETIC DISORDERS IN MADHYA PRADESH, INDIA

2013 ◽  
Vol 5 (1) ◽  
pp. e2013063 ◽  
Author(s):  
R S Balgir
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Genetic Disorders ◽  
Central India ◽  
Thalassemia Major ◽  
Tertiary Hospital ◽  
Physical Distance ◽  
Cell Disease ◽  
Affected Offspring

Background: Recessively inherited genetic disorders such as sickle cell anemia and β-thalassemia are commonly encountered in heterozygous and homozygous form in India. These hemolytic disorders cause a high degree of reproductive wastage in vulnerable communities. Inbreeding is usually the mating between two related individuals. Homozygosis is antagonistic process of heterosis.Purpose: This study was aimed at finding reproductive outcome in carrier couples of sickle cell disease, and β-thalassemia in terms of reproductive wastage in relation to varied marital distance between partners in Madhya Pradesh.Methods: A total of 107 (35 and 72, respectively) carrier couples of β-thalassemia major and sickle cell anemia with confirmed affected offspring after taking detailed reproductive history were studied following the standard methodology in a tertiary hospital in Central India during March 2010 to February 2013.Results: A majority of sickle cell and b-thalassemia carrier couples (77.8% and 65.7%, respectively) had married within physical distance of radius less than 50 kms. away from their native places. It was found that as the marital distance between two carrier partners of above disorders decreases, the number of abortions, still-births, neonatal mortality, infant mortality, and mortality under 10 years age increases, and vice versa, implicating inbreeding and homozygosis. The overall reproductive wastage of 28.2% and 18.6% was recorded in carrier couples of sickle cell disease and β-thalassemia, respectively.Conclusions: Relative small population size clubbed with small marital distance leads to inbreeding resulting in homozygosity which increases chances of affected offspring by recessive or deleterious traits and contributes to decreased fitness of a couple or population in Central India.

scholarly journals Sickle Cell Anemia: A review on the most severe form of Sickle Cell Disease

Bionatura ◽  
2019 ◽  
Vol 02 (Bionatura Conference Serie) ◽  
Author(s):  
María Belén Paredes ◽  
María Eugenia Sulen
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Globin Gene ◽  
Single Point ◽  
Clinical Manifestations ◽  
Severe Form ◽  
Single Point Mutation ◽  
Cell Disease ◽  
Hemoglobin S

Sickle cell disease (SCD) is a group of hereditary disorders caused by a single point mutation in the β-globin gene. This mutation results in the formation of a mutated hemoglobin S (HbS) and the consequent sickle phenotype of erythrocytes. SCD is common in regions of malaria endemicity. However, changes in population dynamics enabled the movement of the mutated gene to other areas such as North America and Europe. Sickle cell anemia (SCA) is the most severe form of SCD and affects millions of people around the globe. The clinical manifestations of SCA arise primarily from the polymerization of deoxygenated hemoglobin S (deoxyHbS) leading to vascular occlusion and hemolytic anemia. Clinical complications of the disease are derived from deoxyHbS polymerization, but there are several therapeutic strategies to reduce the severity of the symptoms. Gene therapy has arisen as a new therapeutic approach aimed to cure rather than to treat the symptomatology of SCA by targeting the altered β-globin gene for gene correction.

Rapid and reliable β-globin gene cluster haplotyping of sickle cell disease patients by FRET Light Cycler and HRM assays

2011 ◽  
Vol 412 (13-14) ◽  
pp. 1257-1261 ◽  
Author(s):  
Philippe Joly ◽  
Philippe Lacan ◽  
Caroline Garcia ◽  
Angelique Delasaux ◽  
Alain Francina
Keyword(s):  
Sickle Cell Disease ◽  
Gene Cluster ◽  
Sickle Cell ◽  
Globin Gene ◽  
Cell Disease ◽  
Globin Gene Cluster ◽  
Light Cycler

scholarly journals 3,3′,5-Triiodothyroacetic acid (TRIAC) induces embryonic ζ-globin expression via thyroid hormone receptor α

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Huiqiao Chen ◽  
Zixuan Wang ◽  
Shanhe Yu ◽  
Xiao Han ◽  
Yun Deng ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Globin Gene ◽  
Erythroid Cells ◽  
Cell Disease ◽  
Potent Inducer ◽  
Thyroid Hormone Receptor Α

AbstractThe human ζ-globin gene (HBZ) is transcribed in primitive erythroid cells only during the embryonic stages of development. Reactivation of this embryonic globin synthesis would likely alleviate symptoms both in α-thalassemia and sickle-cell disease. However, the molecular mechanisms controlling ζ-globin expression have remained largely undefined. Moreover, the pharmacologic agent capable of inducing ζ-globin production is currently unavailable. Here, we show that TRIAC, a bioactive thyroid hormone metabolite, significantly induced ζ-globin gene expression during zebrafish embryogenesis. The induction of ζ-globin expression by TRIAC was also observed in human K562 erythroleukemia cell line and primary erythroid cells. Thyroid hormone receptor α (THRA) deficiency abolished the ζ-globin-inducing effect of TRIAC. Furthermore, THRA could directly bind to the distal enhancer regulatory element to regulate ζ-globin expression. Our study provides the first evidence that TRIAC acts as a potent inducer of ζ-globin expression, which might serve as a new potential therapeutic option for patients with severe α-thalassemia or sickle-cell disease.

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