Association Between Genetic Polymorphisms and Hb F Levels in Heterozygous β-Thalassemia 3.5 kb Deletions

Tepakhan, Wanicha; Kanjanaopas, Sataron; Srewaradachpisal, Korntip

doi:10.1080/03630269.2020.1811117

Cited by 5 publications

(4 citation statements)

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“…It had been previously reported as an unlikely pathogenic SNP (rs2072597) [ 38 ]. The p.F182L variation is also classified as a benign variant (rs2072596) falling in the proline-rich domain and involving a phenylalanine-for-leucine substitution at codon 182 (TTC > CTC) [ 39 , 40 ]. In our study, it has been found in combination with other KLF1 sequence variations in a β-thalassemia heterozygous ( Table 3 , subjects 3) and in two subjects with normal α- and β-globin genotypes.…”

Section: Resultsmentioning

confidence: 99%

Identification and Functional Analysis of Known and New Mutations in the Transcription Factor KLF1 Linked with β-Thalassemia-like Phenotypes

Catapano

Sessa

Trombetti

et al. 2023

Biology

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The erythroid transcriptional factor Krüppel-like factor 1 (KLF1) is a master regulator of erythropoiesis. Mutations that cause KLF1 haploinsufficiency have been linked to increased fetal hemoglobin (HbF) and hemoglobin A2 (HbA2) levels with ameliorative effects on the severity of β-thalassemia. With the aim of determining if KLF1 gene variations might play a role in the modulation of β-thalassemia, in this study we screened 17 subjects showing a β-thalassemia-like phenotype with a slight or marked increase in HbA2 and HbF levels. Overall, seven KLF1 gene variants were identified, of which two were novel. Functional studies were performed in K562 cells to clarify the pathogenic significance of these mutations. Our study confirmed the ameliorative effect on the thalassemia phenotype for some of these variants but also raised the notion that certain mutations may have deteriorating effects by increasing KLF1 expression levels or enhancing its transcriptional activity. Our results indicate that functional studies are required to evaluate the possible effects of KLF1 mutations, particularly in the case of the co-existence of two or more mutations that could differently contribute to KLF1 expression or transcriptional activity and consequently to the thalassemia phenotype.

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Section: Resultsmentioning

confidence: 99%

Identification and Functional Analysis of Known and New Mutations in the Transcription Factor KLF1 Linked with β-Thalassemia-like Phenotypes

Catapano

Sessa

Trombetti

et al. 2023

Biology

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“…Accordingly, this study supports a previous recommendation proposing the inclusion of α 0 -thalassemia analysis in prenatal diagnosis for fetuses affected with thalassemia disease to make appropriate decisions 20 . Previous studies reported that β 0 -thalassemia (3.5 kb deletion) carriers usually exhibit higher Hb A 2 and Hb F levels than other β-thalassemia carriers due to point mutations 21 , 22 . The positive result in reverse dot blot (RDB) hybridization indicating a homozygous Hb Malay genotype in the Hb Malay with β 0 -thalassemia (3.5 kb deletion) case, alongside hematological profiles resembling thalassemia intermedia, raises the possibility of misdiagnosis as homozygous Hb Malay.…”

Section: Discussionmentioning

confidence: 99%

Molecular epidemiology and hematological profiles of hemoglobin variants in southern Thailand

Tepakhan,

Kanjanaopas,

Sreworadechpisal

et al. 2024

Sci Rep

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Data on hemoglobin (Hb) variants in southern Thailand are lacking. This study aimed to reassess the frequency of Hb variants and the clinical aspects of compound heterozygous Hb variant with other hemoglobinopathies. We enrolled 13,391 participants from ten provinces in southern Thailand during 2015–2022. Hb analysis was performed using capillary electrophoresis, and mutations in the HBA and HBB genes were identified using PCR or DNA sequencing. Hb variants were identified in 337 (2.5%) unrelated subjects. Nine β-chain variants, namely Hb Malay (76.9%), Hb C (10.1%), Hb D-Punjab (2.9%), Hb G-Makassar (2.3%), Hb Dhonburi (2.3%), Hb Tak (1.4%), Hb J-Bangkok (1.4%), Hb New York (0.3%), and Hb Hope (0.3%), and four α-chain variants—Hb G-Georgia (HBA1) (0.9%), Hb G-Georgia (HBA2) (0.3%), Hb Q-Thailand (0.6%), and Hb St. Luke’s-Thailand (0.3%)—were identified. The southern population exhibited a distinct spectrum of Hb variants compared to that observed in the populations from other areas. Several compound heterozygous genotypes were also identified. Combining Hb Malay with Hb E or high Hb F determinants did not require a blood transfusion. This study provides essential information for genetic counseling in thalassemia prevention and control programs in this region.

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“…It has been noted that variation preliminarily in the two SNPs, rs4895441 and rs9399137 in HBS1L-MYB intergenic region, may have a small effect on Hb F expression in this β -thalassemia allele ( Tepakhan, Kanjanaopas & Srewaradachpisal, 2020 ). We have also documented that the G allele of rs4895441 and C allele of rs9399137 , alone or in combination with other SNPs, could explain the mild phenotypic expression of NTDT associated with Hb E- β -thalassemia disease ( Phanrahan et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Molecular basis of a high Hb A₂/Hb Fβ-thalassemia trait: a retrospective analysis, genotype-phenotype interaction, diagnostic implication, and identification of a novel interaction withα-globin gene triplication

Soontornpanawet

Singha

Srivorakun

et al. 2023

PeerJ

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Background β0-thalassemia deletion removing 5´β-globin promoter usually presents phenotype with high hemoglobin (Hb) A2 and Hb F levels. We report the molecular characteristics and phenotype-genotype correlation in a large cohort of the β0-thalassemia with 3.4 kb deletion. Methods A total of 148 subjects, including 127 heterozygotes, 20 Hb E-β-thalassemia patients, and a double heterozygote with α-globin gene triplication, were recruited. Hb and DNA analysis were performed to identify thalassemia mutations and four high Hb F single nucleotide polymorphisms (SNPs) including four base pair deletion (-AGCA) at Aγ-globin promoter, rs5006884 on OR51B6 gene, −158 Gγ-XmnI, BCL11A binding motifs (TGGTCA) between 3´Aγ-globin gene and 5´δ-globin gene. Results It was found that heterozygous β0-thalassemia and Hb E-β0-thalassemia with 3.4 kb deletion had significantly higher Hb, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin and Hb F values as compared with those with other mutations. Co-inheritance of heterozygous β0-thalassemia with 3.4 kb deletion and α-thalassemia was associated with even higher MCV and MCH values. The Hb E-β0-thalassemia patients carried a non-transfusion-dependent thalassemia phenotype with an average Hb of around 10 g/dL without blood transfusion. A hitherto undescribed double heterozygous β0-thalassemia with 3.4 kb deletion and α-globin gene triplication presented as a plain β-thalassemia trait. Most of the subjects had wild-type sequences for the four high Hb F SNPs examined. No significant difference in Hb F was observed between those of subjects with and without these SNPs. Removal of the 5´β-globin promoter may likely be responsible for this unusual phenotype. Conclusions The results indicate that β0-thalassemia with 3.4 kb deletion is a mild β-thalassemia allele. This information should be provided at genetic counseling and prenatal thalassemia diagnosis.

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Association Between Genetic Polymorphisms and Hb F Levels in Heterozygous β-Thalassemia 3.5 kb Deletions

Cited by 5 publications

References 35 publications

Identification and Functional Analysis of Known and New Mutations in the Transcription Factor KLF1 Linked with β-Thalassemia-like Phenotypes

Identification and Functional Analysis of Known and New Mutations in the Transcription Factor KLF1 Linked with β-Thalassemia-like Phenotypes

Molecular epidemiology and hematological profiles of hemoglobin variants in southern Thailand

Molecular basis of a high Hb A₂/Hb Fβ-thalassemia trait: a retrospective analysis, genotype-phenotype interaction, diagnostic implication, and identification of a novel interaction withα-globin gene triplication

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Association Between Genetic Polymorphisms and Hb F Levels in Heterozygous β-Thalassemia 3.5 kb Deletions

Cited by 5 publications

References 35 publications

Identification and Functional Analysis of Known and New Mutations in the Transcription Factor KLF1 Linked with β-Thalassemia-like Phenotypes

Identification and Functional Analysis of Known and New Mutations in the Transcription Factor KLF1 Linked with β-Thalassemia-like Phenotypes

Molecular epidemiology and hematological profiles of hemoglobin variants in southern Thailand

Molecular basis of a high Hb A2/Hb Fβ-thalassemia trait: a retrospective analysis, genotype-phenotype interaction, diagnostic implication, and identification of a novel interaction withα-globin gene triplication

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Product

Resources

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Molecular basis of a high Hb A₂/Hb Fβ-thalassemia trait: a retrospective analysis, genotype-phenotype interaction, diagnostic implication, and identification of a novel interaction withα-globin gene triplication