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

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.

Download Full-text

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 ◽

10.1182/blood.v122.21.954.954 ◽

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.

Download Full-text

Alpha globin gene number: population and restriction endonuclease studies

Blood ◽

10.1182/blood.v55.4.706.706 ◽

1980 ◽

Vol 55 (4) ◽

pp. 706-708 ◽

Cited By ~ 27

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)).

Download Full-text

HbS-Sicilian (δβ)0-Thalassemia: A Rare Variant of Sickle Cell

Case Reports in Hematology ◽

10.1155/2017/9265396 ◽

2017 ◽

Vol 2017 ◽

pp. 1-3

Author(s):

Grace Onimoe ◽

Genine Smarzo

Keyword(s):

Sickle Cell Disease ◽

Rare Variant ◽

Sickle Cell ◽

Sickle Cell Trait ◽

Globin Gene ◽

Single Amino Acid ◽

Beta Thalassemia ◽

Cell Disease ◽

Chromosome 11 ◽

Sequencing Studies

Sickle cell disease (SCD) is caused by a mutation in the sixth codon of the β-globin gene on chromosome 11, which leads to a single amino acid substitution (glutamine to valine). Sickle-(δβ)0-thalassemia is a rare variant of sickle cell disease (delta-beta thalassemia occurring in association with sickle hemoglobin, HbS), sparsely reported in literature, and has been associated with symptomatology necessitating careful monitoring and follow-up. We describe a patient who presented with a newborn screen reported as “FS” and a negative family history for sickle cell disease and sickle cell trait. Subsequent gene sequencing studies demonstrated the presence of Sickle-(δβ)0-thalassemia. Clinical course has remained relatively stable for this patient now at 18 months of age without any SCD related symptomatology or complications. As this is a rare variant of SCD with potential complications, it is important to establish diagnosis towards planning comprehensive care.

Download Full-text

Alpha globin gene number: population and restriction endonuclease studies

Blood ◽

10.1182/blood.v55.4.706.bloodjournal554706 ◽

1980 ◽

Vol 55 (4) ◽

pp. 706-708 ◽

Cited By ~ 1

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)).

Download Full-text

Combination of a triple alpha-globin gene with beta-thalassemia in a gypsy family: importance of the genetic testing in the diagnosis and search for a donor for bone marrow transplantation for one of their children

BMC Research Notes ◽

10.1186/s13104-016-2027-1 ◽

2016 ◽

Vol 9 (1) ◽

Cited By ~ 3

Author(s):

Flor Yus Cebrian ◽

María del Valle Recasens Flores ◽

Silvia Izquierdo Álvarez ◽

Ingrid Parra Salinas ◽

Carmen Rodriguez-Vigil Iturrate

Keyword(s):

Bone Marrow ◽

Genetic Testing ◽

Bone Marrow Transplantation ◽

Marrow Transplantation ◽

Globin Gene ◽

Beta Thalassemia ◽

Alpha Globin ◽

Triple Alpha

Download Full-text

Beta zero-thalassemia in association with a gamma-globin gene quadruplication

Blood ◽

10.1182/blood.v68.6.1394.bloodjournal6861394 ◽

1986 ◽

Vol 68 (6) ◽

pp. 1394-1397

Author(s):

KG Yang ◽

JZ Liu ◽

F Kutlar ◽

A Kutlar ◽

C Altay ◽

...

Keyword(s):

Clinical Condition ◽

Globin Gene ◽

Normal Chromosome ◽

Gene Arrangement ◽

Beta Thalassemia ◽

Globin Genes ◽

Thalassemia Intermedia ◽

Gamma Globin ◽

Alpha Globin

We have studied the hematology, hemoglobin composition, and globin gene arrangements in one young Turkish boy with a beta zero-thalassemia homozygosity and in 11 of his relatives. Evidence is presented that the chromosome with the beta zero-thalassemia determinant carries a gamma- globin gene quadruplication, perhaps in a -G gamma-G gamma-G gamma-A gamma-gene arrangement. The eight gamma-globin genes in this patient produced G gamma and A gamma chains in a 95 to 5 ratio, and nearly 99% of the patient's hemoglobin was of the fetal type. The clinical condition resembled that of a thalassemia intermedia. HbF levels in eight beta-thalassemia heterozygotes varied between 0.5 and 4.2% and the percentages of G gamma in this HbF averaged at 87% or 95%; this level is to some extent related to the haplotype of the normal chromosome. All subjects carried four alpha-globin genes; a new BglII polymorphism was observed within the psi alpha-globin gene.

Download Full-text

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 ◽

10.1182/blood.v85.4.1111.bloodjournal8541111 ◽

1995 ◽

Vol 85 (4) ◽

pp. 1111-1117 ◽

Cited By ~ 79

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).

Download Full-text

A family with segregating triplicated alpha globin loci and beta thalassemia

Blood ◽

10.1182/blood.v62.5.1035.1035 ◽

1983 ◽

Vol 62 (5) ◽

pp. 1035-1040 ◽

Cited By ~ 57

Author(s):

R Galanello ◽

R Ruggeri ◽

E Paglietti ◽

M Addis ◽

MA Melis ◽

...

Keyword(s):

Globin Gene ◽

Phenotypic Expression ◽

Beta Thalassemia ◽

Heterozygous State ◽

Globin Chain ◽

Homozygous State ◽

Alpha Globin ◽

Triple Alpha ◽

Chain Synthesis ◽

Globin Chain Synthesis

Abstract In this article we report a Sardinian family, in which a beta- thalassemia gene and a triple alpha-globin loci, counterpart of the rightward deletion type alpha-thalassemia-2, were segregating. The analysis of the genotype-phenotype correlations in the different family members allowed us to give an outline of the manifestations associated with different genotype combinations. The heterozygote for the triple alpha-loci showed no consistent abnormal clinical or hematologic characteristics and presented balanced alpha/beta-globin chain synthesis. In the homozygous state for this lesion, the only phenotypic expression was a slightly imbalanced globin chain synthesis. The combination of heterozygous beta-thalassemia with the heterozygous state for the triple alpha-globin loci produced no clinical manifestations and showed a hematologic phenotype indistinguishable from that of heterozygous beta-thalassemia. On the other hand, the combination of the homozygous state for the triple alpha-globin gene loci and the heterozygous state for beta-thalassemia produced a clinical picture of thalassemia intermedia with a very mild clinical course, minor increase of fetal hemoglobin (HbF) levels, and a pronounced imbalance of globin chain synthesis.

Download Full-text

Hydroxyurea increases hemoglobin F levels and improves the effectiveness of erythropoiesis in beta-thalassemia/hemoglobin E disease

Blood ◽

10.1182/blood.v87.3.887.bloodjournal873887 ◽

1996 ◽

Vol 87 (3) ◽

pp. 887-892 ◽

Cited By ~ 88

Author(s):

S Fucharoen ◽

N Siritanaratkul ◽

P Winichagoon ◽

J Chowthaworn ◽

W Siriboon ◽

...

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Beta Thalassemia ◽

Limited Information ◽

Cell Disease ◽

Hemoglobin F ◽

Hemoglobin E ◽

Globin Chains ◽

Hb E ◽

Alpha Globin

Hydroxyurea (HU) is one of several agents that have been shown to enhance hemoglobin (Hb) F levels in patients with sickle cell disease and may be useful as a therapy for beta-globinopathies. However, limited information exists on the effects of HU in patients with thalassemia. Accordingly, we examined the hematologic effects of orally administered HU in 13 patients with beta-thalassemia/Hb E, including four patients who had been splenectomized. These patients were treated with escalating doses (final range, 10 to 20 mg/kg/d) for 5 months and were observed in the outpatient hematology clinic every 2 to 4 weeks. Complete blood counts including reticulocyte counts, amounts of Hb E and Hb F, G gamma:A gamma and alpha:non-alpha globin biosynthetic ratios were evaluated before and during treatment. Almost all patients responded with an average increase of 33% in Hb F levels, from a mean (+/- SD) of 42% +/- 11% to 56% +/- 8% (P < .0001), and a reciprocal decline in the percentage of Hb E from 59% +/- 9% to 49% +/- 8% (P < .001). Reticulocytosis was decreased from a mean (+/- SD) of 18.0% +/- 15.6% to 11.7% +/- 9.1% (P < .05); there was also a slight (10%) but statistically significant increase in hemoglobin levels and an improved balance in alpha:non-alpha globin chains ratios. The side effects were minimal in most patients, although these patients tended to tolerate a lower dose of HU before significant myelosuppression than has been our previous experience in sickle cell disease. One splenectomized patient died of sepsis during the trial. We conclude that increased Hb F production in beta-thalassemia/Hb E patients, with an improvement in the alpha:non-alpha globin ratios and, probably, the effectiveness of erythropoiesis, can be achieved using HU. Longer trials of HU in this population, including at other doses and in combination with other agents, appear warranted.

Download Full-text