scholarly journals Alpha globin gene number: population and restriction endonuclease studies

Blood ◽  
1980 ◽  
Vol 55 (4) ◽  
pp. 706-708 ◽  
Author(s):  
G Brittenham ◽  
B Lozoff ◽  
JW Harris ◽  
YW Kan ◽  
AM Dozy ◽  
...  
Keyword(s):  
Restriction Endonuclease ◽  
Sickle Cell ◽  
Genetic Model ◽  
Sickle Cell Trait ◽  
Globin Gene ◽  
Restriction Endonuclease Analysis ◽  
Globin Genes ◽  
Gene Number ◽  
Alpha Globin ◽  
Study Population

Abstract Restriction endonuclease analysis was used to test a proposed genetic model using alpha-globin gene number to account for the observed distributions of the proportions of hemoglobin (Hb) S in sickle cell trait. In a subsample of specimens collected during a population survey in India, these studies confirmed that the postulated genotype was present in 22 of the 23 individuals examined. In the study population, the number of alpha-globin genes explains about 90% of the variance in the proportion of HbS in sickle cell trait (r2 = 0.895, p less than 10(- 10)).

scholarly journals Alpha globin gene number: population and restriction endonuclease studies

Blood ◽  
1980 ◽  
Vol 55 (4) ◽  
pp. 706-708 ◽  
Author(s):  
G Brittenham ◽  
B Lozoff ◽  
JW Harris ◽  
YW Kan ◽  
AM Dozy ◽  
...  
Keyword(s):  
Restriction Endonuclease ◽  
Sickle Cell ◽  
Genetic Model ◽  
Sickle Cell Trait ◽  
Globin Gene ◽  
Restriction Endonuclease Analysis ◽  
Globin Genes ◽  
Gene Number ◽  
Alpha Globin ◽  
Study Population

Restriction endonuclease analysis was used to test a proposed genetic model using alpha-globin gene number to account for the observed distributions of the proportions of hemoglobin (Hb) S in sickle cell trait. In a subsample of specimens collected during a population survey in India, these studies confirmed that the postulated genotype was present in 22 of the 23 individuals examined. In the study population, the number of alpha-globin genes explains about 90% of the variance in the proportion of HbS in sickle cell trait (r2 = 0.895, p less than 10(- 10)).

scholarly journals An analysis of fetal hemoglobin variation in sickle cell disease: the relative contributions of the X-linked factor, beta-globin haplotypes, alpha-globin gene number, gender, and age

Blood ◽  
1995 ◽  
Vol 85 (4) ◽  
pp. 1111-1117 ◽  
Author(s):  
YC Chang ◽  
KD Smith ◽  
RD Moore ◽  
GR Serjeant ◽  
GJ Dover
Keyword(s):  
Sickle Cell ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Globin Genes ◽  
Beta Globin ◽  
Gene Number ◽  
Cohort Group ◽  
Five Factors ◽  
F Cells ◽  
Alpha Globin

Five factors have been shown to influence the 20-fold variation of fetal hemoglobin (Hb F) levels in sickle cell anemia (SS): age, sex, the alpha-globin gene number, beta-globin haplotypes, and an X-linked locus that regulates the production of Hb F-containing erythrocytes (F cells), ie, the F-cell production (FCP) locus. To determine the relative importance of these factors, we studied 257 Jamaican SS subjects from a Cohort group identified by newborn screening and from a Sib Pair study. Linear regression analyses showed that each variable, when analyzed alone, had a significant association with Hb F levels (P < .05). Multiple regression analysis, including all variables, showed that the FCP locus is the strongest predictor, accounting for 40% of Hb F variation. beta-Globin haplotypes, alpha-globin genes, and age accounted for less than 10% of the variation. The association between the beta-globin haplotypes and Hb F levels becomes apparent if the influence of the FCP locus is removed by analyzing only individuals with the same FCP phenotype. Thus, the FCP locus is the most important factor identified to date in determining Hb F levels. The variation within each FCP phenotype is modulated by factors associated with the three common beta-globin haplotypes and other as yet unidentified factor(s).

Influence of Globin Gene Modifiers on Baseline and Hydroxyurea-Induced Fetal Hemoglobin Levels in Children with Sickle Cell Anemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3171-3171
Author(s):  
Russell E. Ware ◽  
Barry Eggleston ◽  
Tatiana Abramova ◽  
Sherri A. Zimmerman ◽  
Alice Lail ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Globin Genes ◽  
Beta Globin ◽  
Gene Number ◽  
Gamma Globin ◽  
Alpha Globin ◽  
Hydroxyurea Therapy

Abstract Fetal hemoglobin (HbF) is recognized as a major determinant of clinical disease severity in children and adults with sickle cell anemia (SCA). Patients with elevated HbF levels have a milder disease course, and many current therapeutic protocols for SCA include pharmacological induction of HbF. However, baseline and treatment HbF levels vary widely due to presumed genetic and environmental factors. Recognized globin gene modifiers of HbF include the beta globin haplotype and a potential contribution from concomitant alpha thalassemia. To characterize more fully the influence of globin gene modifiers on both baseline and treatment HbF levels, we retrospectively determined the beta globin haplotype (Benin, CAR, Senegal, Cameroon, or Arab-Indian) by selective gamma globin gene nucleotide sequencing and the alpha globin gene number (2, 3, or 4) by PCR for 67 African-American children with SCA receiving hydroxyurea therapy at stable maximal tolerated dose (MTD). The four beta globin haplotypes and frequencies identified in our cohort of children include Benin (0.61), CAR (0.17), Senegal (0.12), and Cameroon (0.10). The number of alpha globin genes and frequencies identified were 4 genes (0.72), 3 genes (0.25) and 2 genes (0.03). Baseline and MTD HbF levels were analyzed according to each variable. The average baseline HbF value for the entire cohort of children was 7.7 ± 4.4% (median 7.6%, range 1.3 – 19.3%), while the average treatment HbF value was 23.9 ± 7.2 % (median 22.9%, range 10.2 – 40.7%). All 67 children increased their HbF in response to hydroxyurea therapy (median 16.7%, range 5.0 – 28.8%). There was a modest but statistically significant correlation between the baseline and treatment HbF (r=0.66, p&lt;.0001). The estimated effect of one unit change in baseline HbF on treatment HbF was 1.11 (95% CI of 0.78, 1.43). When baseline %HbF was analyzed according to the beta globin haplotype, the overall ANOVA had a p-value of 0.02, indicating a statistically significant influence. Further analysis confirmed associations previously identified in adults with SCA, i.e. children with at least one copy of the CAR haplotype had a lower baseline HbF (5.9% vs 8.4%, p=.05), while those with at least one copy of the Senegal haplotype had a higher baseline HbF (11.1% vs 6.7%, p&lt;.001). When hydroxyurea MTD (treatment) HbF values were analyzed according to beta globin haplotype while adjusting for baseline HbF, however, the effect of beta globin haplotype was not statistically significant (p=.13). Analyses of HbF according to alpha globin gene number revealed no statistically significant effects on either baseline or treatment HbF values. Taken together, these data support the hypothesis that beta globin haplotype significant influences baseline HbF values for children with SCA, but has no significant effects on hydroxyurea MTD HbF values. Accordingly, children with SCA should be offered hydroxyurea based solely on clinical indications, without consideration of baseline HbF or beta globin haplotype. Even children with low baseline HbF values or the CAR beta globin haplotype can respond to hydroxyurea therapy with an elevated %HbF. Future studies designed to identify genetic modifiers of treatment HbF values should focus on sequence polymorphisms in non-globin genes that have trans-acting effects on gamma globin gene expression.

scholarly journals The cellular basis for different fetal hemoglobin levels among sickle cell individuals with two, three, and four alpha-globin genes

Blood ◽  
1987 ◽  
Vol 69 (1) ◽  
pp. 341-344 ◽  
Author(s):  
GJ Dover ◽  
VT Chang ◽  
SH Boyer ◽  
GR Serjeant ◽  
S Antonarakis ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Enrichment Ratio ◽  
Globin Genes ◽  
Cell Production ◽  
Gene Number ◽  
Alpha Thalassemia ◽  
F Cells ◽  
Alpha Globin

Fetal hemoglobin (HbF) levels vary widely among individuals with sickle cell anemia (SS). Previous studies have suggested that HbF levels in SS individuals with alpha-thalassemia (two or three functional alpha- globin genes) are lower than HbF levels in SS individuals with four normal alpha-globin genes. Using immunocytochemical techniques, we studied F cell production as measured by % F reticulocytes, the amount of HbF per F cell, and the preferential survival of F cells versus non- F cells in 51 subjects with four alpha genes, 32 subjects with three alpha genes, and 18 subjects with two alpha genes. Comparison between alpha-globin gene groups was performed for the total sample as well as for a subset of 82 individuals who had replicate samples and a further subset of 39 age-matched individuals. %HbF levels were 6.8, 4.9, and 4.5 percent for the total four-, three-, and two-alpha-globin-gene groups, respectively. The percentage of F reticulocytes, percentage HbF per F cell, and the enrichment ratio (% F cell/% F reticulocytes) did not change significantly with alpha-globin gene number. Moreover, no correlation existed between alpha-globin gene number and the absolute number of F cells in any group studied. However, there was a strong inverse correlation (r = -0.407, P = .0001) between non-F cell levels (1.7 +/- 2, 2.2 +/- 5, 3.0 +/- 1.0 X 10(12)/L) and decreasing alpha- globin gene number. These data suggest that falling HbF levels among SS individuals with lessened numbers of alpha-globin genes reflect prolonged survival of non-F cells and are not due to intrinsic differences in F cell production or in the amount of HbF per F cell. The improved survival of non-F cells in SS alpha-thalassemia is presumed to be due to the lower MCHC observed in such individuals.

scholarly journals The cellular basis for different fetal hemoglobin levels among sickle cell individuals with two, three, and four alpha-globin genes

Blood ◽  
1987 ◽  
Vol 69 (1) ◽  
pp. 341-344 ◽  
Author(s):  
GJ Dover ◽  
VT Chang ◽  
SH Boyer ◽  
GR Serjeant ◽  
S Antonarakis ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Enrichment Ratio ◽  
Globin Genes ◽  
Cell Production ◽  
Gene Number ◽  
Alpha Thalassemia ◽  
F Cells ◽  
Alpha Globin

Abstract Fetal hemoglobin (HbF) levels vary widely among individuals with sickle cell anemia (SS). Previous studies have suggested that HbF levels in SS individuals with alpha-thalassemia (two or three functional alpha- globin genes) are lower than HbF levels in SS individuals with four normal alpha-globin genes. Using immunocytochemical techniques, we studied F cell production as measured by % F reticulocytes, the amount of HbF per F cell, and the preferential survival of F cells versus non- F cells in 51 subjects with four alpha genes, 32 subjects with three alpha genes, and 18 subjects with two alpha genes. Comparison between alpha-globin gene groups was performed for the total sample as well as for a subset of 82 individuals who had replicate samples and a further subset of 39 age-matched individuals. %HbF levels were 6.8, 4.9, and 4.5 percent for the total four-, three-, and two-alpha-globin-gene groups, respectively. The percentage of F reticulocytes, percentage HbF per F cell, and the enrichment ratio (% F cell/% F reticulocytes) did not change significantly with alpha-globin gene number. Moreover, no correlation existed between alpha-globin gene number and the absolute number of F cells in any group studied. However, there was a strong inverse correlation (r = -0.407, P = .0001) between non-F cell levels (1.7 +/- 2, 2.2 +/- 5, 3.0 +/- 1.0 X 10(12)/L) and decreasing alpha- globin gene number. These data suggest that falling HbF levels among SS individuals with lessened numbers of alpha-globin genes reflect prolonged survival of non-F cells and are not due to intrinsic differences in F cell production or in the amount of HbF per F cell. The improved survival of non-F cells in SS alpha-thalassemia is presumed to be due to the lower MCHC observed in such individuals.

scholarly journals Potential Impact of Sickle Hemoglobin Concentration on Survival Among Patients with Renal Medullary Carcinoma and Sickle Cell Trait

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4843-4843
Author(s):  
Marcus A. Carden ◽  
Jonathan Metts ◽  
John M. McCarty ◽  
Sarah Mitchell ◽  
Bradley Carthon ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Survival Data ◽  
Sickle Cell Trait ◽  
Case Reports ◽  
Globin Gene ◽  
Medullary Carcinoma ◽  
Exponential Relationship ◽  
Sickle Hemoglobin ◽  
Renal Medullary Carcinoma ◽  
Alpha Globin

Background: Renal medullary carcinoma (RMC) is a rare, aggressive form of renal cell carcinoma almost exclusively (>90%) diagnosed in individuals with sickle cell trait (SCT), and 2/3 of those affected are male. Based on population-surveillance data, only 246 patients were diagnosed with RMC between 2005-2014 (Carden etal. J Sickle Cell Disease and Hemoglobinopathies, 2018) and many patients have metastatic disease at diagnosis (Msaeoul et al., Clin Genitourin Cancer, 2019). Median overall survival (OS) in patients with metastatic RMC (mRMC) at diagnosis is less than 12 months and predictors of survival are largely unknown, although case reports suggest novel chemotherapeutic strategies are important (Carden et al., Ped Blood Cancer, 2017&2018). The role SCT plays in RMC pathobiology, however, is largely unknown, as many patients do not have a complete hemoglobin subtype profile completed at diagnosis. Studies evaluating sickle hemoglobin concentrations (%HbS) in relation to survival for patients with RMC are needed, as SCT is associated with renal dysfunction and researchers have hypothesized that HbS polymerization within red cells traversing the kidney disrupts blood perfusion, which leads to kidney injury and an increased possibility for cancer formation (Msaeoul et al, Clin Cancer Res, 2018). Patients with %HbS≤36%, such as patients with SCT and concomitant alpha-globin gene deletion(s) might be protected against HbS polymerization and renal concentrating defects (Gupta etal., J Clin Invest, 1991). We hypothesize that lower %HbS is associated with higher survival. In this preliminary multi-institutional study, we retrospectively reviewed available charts from patients diagnosed with mRMC and SCT to evaluate for an association between %HbS and OS. Methods: We found nine patients (3 adults, 6 children) who were diagnosed with mRMC and SCT at our various institutions between 2002-2017 who had survival data. Eight patients had %HbS levels by hemoglobin quantification at diagnosis. In a post-hoc analysis, patients were separated into two groups (%HbS>36% and %HbS≤36%), levels similar to that found in patients with alpha-globin gene deletions described by Gupta et al. Fit-curves were determined for OS vs. %HbS. Three-year OS was determined using Kaplan-Meier analysis and the log-rank method. P<0.05 was considered statistically significant. Results: Clinical characteristics of patients are shown in Table 1. Average age (standard deviation) at diagnosis was 15.2 years (4.9) and most patients were male (87.5%). Six patients had %HbS >36% and 2 patients had %HbS ≤36%. Median OS was 17.8 months. Using fit-function testing, analysis of survival vs. %HbS yielded an exponential relationship (R2=0.69), suggesting higher survival when %HbS≤36% (p=0.05). OS of the two patients with %HbS≤36% was greater than those with %HbS>36%, though results were not statistically significant (p = 0.09). Conclusion: While there are limitations to this small, retrospective analysis, these data suggest that lower intracellular red cell %HbS concentrations could be protective in patients with mRMC and SCT. Chemotherapy and other treatment regimens may also play a role in survival and need to be studied. Further investigation is needed to determine the role SCT plays in RMC pathobiology and to determine if %HbS concentrations, as well as alpha-thalassemia deletion(s), may be protective in patients with RMC. Disclosures Carden: GBT: Honoraria; NIH: Research Funding.

A Novel β Globin Gene Mutation, Reported As An α Chain Hemoglobin Variant By High Performance Liquid Chromatography (HPLC) & As Sickle Cell Trait On New Born Screening: A case Report

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 954-954
Author(s):  
Kranthi Nandan Seelaboyina ◽  
Jennifer Alison Busse ◽  
Sandeep Malik ◽  
Thomas Moulton
Keyword(s):  
Sickle Cell ◽  
Copy Number ◽  
Sickle Cell Trait ◽  
Globin Gene ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Thalassemia Intermedia ◽  
Exon 2 ◽  
Alpha Globin ◽  
Hemoglobin Variants

Abstract Introduction There are 827 variants of β thalassemia reported to the registry of human hemoglobin variants and thalassemias registry 1. Genetic mutations of β thalassemia are very diverse but can be broadly divided in to non deletion forms and deletion forms. The new mutation is a frame shift insertion in exon 2 of the β globin gene. To the best of our knowledge this mutation has never been described before and presents as a mild form β thalassemia intermedia. Objective To describe the phenotypic presentation of the new β globin variant, due to insertion of 9 nucleotides (AAAGTGCTC) between nucleotides c.207 and c.208. Case report A 22 months-old Hispanic boy who was referred for evaluation of persistent anemia. The new born screening for the child was positive for sickle cell trait. Initial hemoglobin (Hb) was 8.8, hematocrit was 27 and MCV was 65.5, which were decreased. RDW was 25.2, which was increased. Hemoglobin evaluation by acid and alkaline electrophoresis and HPLC revealed a HbS 0%, HbF 6.5% HbA 78.4%, HbA2 4.9% and a Hb variant 10.2%. The interpretation of the results was an α globin variant suggestive of Hb Montefiore and β thalassemia trait. Alpha thalassemia PCR for the 7 most common deletions in the α globin chain was negative. Subsequent α globin gene sequencing revealed no α globin gene mutations. On physical exam there were no bony changes or hepatosplenomegaly. Family History The mother is 29-year-old with HbAA. The father is 39-years-old with the same mutation on beta globin gene analysis. Hb electrophoresis also suggested an α and β globin mutation. Alpha thalassemia PCR was negative and he had a normal α globin gene copy number. At age 19 he had a splenectomy secondary to splenomegaly and hypersplenism. He is consistently anemic with Hb< 9 and MCV < 70. The child has a paternal half brother, who is 21 years old and has similar problems as father. He had a splenectomy at the age of 17 after admission for abdominal pain. The patient has a 5-year-old sibling, who is normal with HbAA and another paternal half sibling reported as no anemia. Discussion Though β thalassemia intermedia is most commonly homozygous or compound heterozygous, less frequently it can be due to single locus mutation. DNA sequencing of the α globin gene of the index case was completely normal and there was normal copy number of the α globin gene in the father. No Hb S was found on Hb electrophoresis. The new mutation adds 9 base pairs to exon 2 and 3 amino acids (Lys-Val-Leu) between amino acid 68 and 69 of the protein. This elongates the beta chain which can lead to instability and precipitation of Hb as well as hemolysis and anemia2. Further studies like short time incubation and pulse chase globin chain synthesis experiments are needed to know the stability of the β globin protein3. In addition, an increase of α globin gene copy number can also be a reason for increasing the severity of β thalassemia trait2. However the α gene copy was normal in the father. Conclusion We present a case of a child with a false positive abnormal newborn screen suggestive of sickle cell trait, as well as a Hb electrophoresis suggestive of an alpha globin mutation. As the father and paternal brother have had a splenectomy in their teen years with noted hepatosplenomegaly, suggestive of increased hemolysis, and the anemia is more severe than usual for β thalassemia trait, this suggests that phenotypically the c.199_207dup variant presents as a mild β thalassemia intermedia. In addition, there does not seem to be any bony abnormalities associated with marrow hyperplasia. As both our patients are heterozygous for this novel mutation with normal α globin gene copy number and alpha globin sequencing, we suspect that elongation of the β globin produces an unstable hemoglobin with a mild β thalassemia intermedia phenotype2. References 1. Databases of human hemoglobin variants and other resources at the globin gene server. Hemoglobin. 25(2):183-93, 2001 May. 2. Galanello R, Cao A. Relationship between genotype and phenotype. Thalassemia intermedia. Annals of the New York Academy of Sciences 1998; 850:325-33. 3. Is hemoglobin instability important in the interaction between hemoglobin E and beta thalassemia? Blood September 15, 1998 vol. 92 no. 6 2141-2146. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Alpha‐globin gene triplication and its effect in beta‐thalassemia carrier, sickle cell trait, and healthy individual

eJHaem ◽  
2021 ◽  
Author(s):  
Mohammad Hamid ◽  
Bijan keikhaei ◽  
Hamid Galehdari ◽  
Alihossein Saberi ◽  
Alireza Sedaghat ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Healthy Individual ◽  
Sickle Cell Trait ◽  
Globin Gene ◽  
Beta Thalassemia ◽  
Alpha Globin

scholarly journals Fetal hemoglobin levels and beta s globin haplotypes in an Indian populations with sickle cell disease

Blood ◽  
1987 ◽  
Vol 69 (6) ◽  
pp. 1742-1746
Author(s):  
AE Kulozik ◽  
BC Kar ◽  
RK Satapathy ◽  
BE Serjeant ◽  
GR Serjeant ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Sickle Cell Trait ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Globin Genes ◽  
Cell Disease ◽  
Hemoglobin F ◽  
S Haplotype ◽  
Asian Populations

To further explore the cause for variation in hemoglobin F (Hb F) levels in sickle cell disease, the beta globin restriction-fragment length polymorphism haplotypes were determined in a total of 303 (126 SS, 141 AS, 17 S beta degrees, 7 A beta, degrees and 12 AA) Indians from the state of Orissa. The beta s globin gene was found to be linked almost exclusively to a beta S haplotype ( -++-), which is also common in Saudi Arabian patients from the Eastern Province (referred to as the Asian beta s haplotype). By contrast, the majority of beta A and beta degree thalassemia globin genes are linked to haplotypes common in all European and Asian populations (+-----[+/-]; --++-++). Family studies showed that there is a genetic factor elevating Hb F levels dominantly in homozygotes (SS). This factor appears to be related to the Asian beta s globin haplotype, and a mechanism for its action is discussed. There is also a high prevalence of an independent Swiss type hereditary persistence of fetal hemoglobin (HPFH) determinant active in both the sickle cell trait and in sickle cell disease.

scholarly journals Fetal hemoglobin levels and beta s globin haplotypes in an Indian populations with sickle cell disease

Blood ◽  
1987 ◽  
Vol 69 (6) ◽  
pp. 1742-1746 ◽  
Author(s):  
AE Kulozik ◽  
BC Kar ◽  
RK Satapathy ◽  
BE Serjeant ◽  
GR Serjeant ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Sickle Cell Trait ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Globin Genes ◽  
Cell Disease ◽  
Hemoglobin F ◽  
S Haplotype ◽  
Asian Populations

Abstract To further explore the cause for variation in hemoglobin F (Hb F) levels in sickle cell disease, the beta globin restriction-fragment length polymorphism haplotypes were determined in a total of 303 (126 SS, 141 AS, 17 S beta degrees, 7 A beta, degrees and 12 AA) Indians from the state of Orissa. The beta s globin gene was found to be linked almost exclusively to a beta S haplotype ( -++-), which is also common in Saudi Arabian patients from the Eastern Province (referred to as the Asian beta s haplotype). By contrast, the majority of beta A and beta degree thalassemia globin genes are linked to haplotypes common in all European and Asian populations (+-----[+/-]; --++-++). Family studies showed that there is a genetic factor elevating Hb F levels dominantly in homozygotes (SS). This factor appears to be related to the Asian beta s globin haplotype, and a mechanism for its action is discussed. There is also a high prevalence of an independent Swiss type hereditary persistence of fetal hemoglobin (HPFH) determinant active in both the sickle cell trait and in sickle cell disease.

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