Molecular Mechanism of High Hemoglobin F Production in Southeast Asian-Type Hereditary Persistence of Fetal Hemoglobin

Changsri, Khaimuk; Akkarapathumwong, Varaporn; Jamsai, Duangporn; Winichagoon, Pranee; Fucharoen, Suthat

doi:10.1532/ijh97.e0509

Cited by 13 publications

(15 citation statements)

References 38 publications

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“…In studies of the genetic regulation of HbA 2 in sickle cell anaemia, an additional association between polymorphisms within the HBB gene cluster and HbA 2 levels that were not mediated through HbF was also found (Griffin et al , ). The variant associated with HbA 2 was 3′ to HBB in the 3′ hypersensitive site that was proposed as an insulator against γ‐globin gene enhancers (Changsri et al , ). It is not clear how, or even if, this single nucleotide polymorphism (SNP) might affect HBD expression.…”

Section: Evolution Synthesismentioning

confidence: 99%

HbA₂: biology, clinical relevance and a possible target for ameliorating sickle cell disease

Steinberg

Rodgers

2015

Br J Haematol

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SummaryHbA 2 , a tetramer of a-and d-globin chains, provides a diagnostic clue to the presence of b-thalassaemia trait. This minor haemoglobin, which forms about 2-3% of the total, has no known physiological role, but has the interesting property of preventing polymerization of deoxy-sickle haemoglobin. If it were possible to increase the level of HbA 2 sufficiently it could have a benefit in sickle cell disease similar to that of foetal haemoglobin. Moreover, HbA 2 is present in all erythrocytes, an advantage not found with foetal haemoglobin, which is heterocellularly expressed. The molecular basis of HbA 2 gene (HBD) expression is partially understood, and with new molecular tools, it might be possible to induce levels of HbA 2 that could be clinically important. However, high concentrations of this positively charged haemoglobin might damage the erythrocyte membrane; also, the reciprocal relationship of d-and c-globin gene (HBD and HBG1/2, respectively) expression might negate any benefit of increasing transcription of the former.

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Section: Evolution Synthesismentioning

confidence: 99%

HbA₂: biology, clinical relevance and a possible target for ameliorating sickle cell disease

Steinberg

Rodgers

2015

Br J Haematol

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“…The most common beta globin gene cluster deletion are Chinese G γ + ( A γδβ) 0 -thalassemia and Southeast Asian hereditary persistence of fetal hemoglobin (SEA-HPFH) in the Chinese population [8]. The deletion length of SEA-HPFH is about 27 kb, and the range includes the β-gene of the β-globin gene cluster and its 3-HS-1 region [9]. The SEA-HPFH heterozygotes have no clinical symptoms, and hematological parameters are in the normal range or in borderline level.…”

Section: Introductionmentioning

confidence: 99%

Genetic research and clinical analysis of deletional Chinese Gγ+(Aγδβ)0 -thalassemia and Southeast Asian HPFH in South China

Wu¹,

Yao²,

Zhong³

et al. 2020

Ann Hematol

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Chinese Gγ+(Aγδβ)0-thalassemia and SEA-HPFH are the most common types of β-globin gene cluster deletion in Chinese population. The aim of the study was to analyze clinical features of deletional Chinese Gγ+(Aγδβ)0-thalassemia and Southeast Asian hereditary persistence of fetal hemoglobin (SEA-HPFH) in South China. A total of 930 subjects with fetal hemoglobin (HbF) level ≥ 2% were selected on genetic research of Chinese Gγ+(Aγδβ)0-thalassemia and SEA-HPFH. The gap polymerase chain reaction was performed to identify the deletions. One hundred cases of Chinese Gγ+(Aγδβ)0-thalassemia were detected, including 90 cases of Chinese Gγ+(Aγδβ)0/βN-thalassemia, 7 cases of Chinese Gγ+(Aγδβ)0 /βN-thalassemia combined with α-thalassemia, 2 cases of Chinese Gγ+(Aγδβ)0-thalassemia combined with β-thalassemia, and 1 case of Chinese Gγ+(Aγδβ)0-thalassemia combined with β-gene mutation. One hundred nine cases of SEA-HPFH were detected, including 97 cases of SEA-HPFH/βN, 9 cases of SEA-HPFH/βN combined with α-thalassemia, 2 cases of SEA-HPFH combined with β-thalassemia, and 1 case of SEA-HPFH combined with β-gene mutation. Statistical analysis indicates significant differences in MCV (mean corpuscular volume), MCH (mean corpuscular hemoglobin), and HbA2 and HbF levels between Chinese Gγ+(Aγδβ)0-thalassemia heterozygotes and SEA-HPFH heterozygotes (P < 0.001). There are statistical differences in hematological parameters between them. Clinical phenotypic analysis can provide guidance for genetic counseling and prenatal diagnosis.

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“…Even a heterozygous deletion can result in HbF level of 65.6% with 8.9 g/dl of hemoglobin on coinheritance with β-thalassemia (19).…”

Section: Discussionmentioning

confidence: 99%

Editing the core region in HPFH deletions alters fetal and adult globin expression for treatment of β-hemoglobinopathies

Venkatesan

Christopher

Babu

et al. 2022

Preprint

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Reactivation of fetal hemoglobin (HbF) is the commonly adapted strategy to ameliorate β-hemoglobinopathies. However, the continued production of defective adult hemoglobin (HbA) limits the HbF tetramer production affecting the therapeutic benefits. Here, we tested various deletional hereditary persistence of fetal hemoglobin (HPFH) mutations and identified a 11 kb sequence, encompassing Putative Repressor Region (PRR) to β-globin Exon-1 (βE1), as the core deletion that ablates HbA and exhibit superior production of HbF compared to HPFH or other well-established targets. The PRR-βE1 edited hematopoietic stem and progenitor cells (HSPCs) retained engraftment potential to repopulate for long-term hematopoiesis in immunocompromised mice generating HbF+ cells in vivo. Importantly, the editing induces therapeutically relevant levels of HbF to reverse the phenotypes of both sickle cell disease and β-thalassemia major. These results indicate that the PRR-βE1 gene editing in patient HSPCs can potentially lead to superior therapeutic outcomes for β-hemoglobinopathies gene therapy.

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Molecular Mechanism of High Hemoglobin F Production in Southeast Asian-Type Hereditary Persistence of Fetal Hemoglobin

Cited by 13 publications

References 38 publications

HbA₂: biology, clinical relevance and a possible target for ameliorating sickle cell disease

HbA₂: biology, clinical relevance and a possible target for ameliorating sickle cell disease

Genetic research and clinical analysis of deletional Chinese Gγ+(Aγδβ)0 -thalassemia and Southeast Asian HPFH in South China

Editing the core region in HPFH deletions alters fetal and adult globin expression for treatment of β-hemoglobinopathies

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Molecular Mechanism of High Hemoglobin F Production in Southeast Asian-Type Hereditary Persistence of Fetal Hemoglobin

Cited by 13 publications

References 38 publications

HbA2: biology, clinical relevance and a possible target for ameliorating sickle cell disease

HbA2: biology, clinical relevance and a possible target for ameliorating sickle cell disease

Genetic research and clinical analysis of deletional Chinese Gγ+(Aγδβ)0 -thalassemia and Southeast Asian HPFH in South China

Editing the core region in HPFH deletions alters fetal and adult globin expression for treatment of β-hemoglobinopathies

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HbA₂: biology, clinical relevance and a possible target for ameliorating sickle cell disease

HbA₂: biology, clinical relevance and a possible target for ameliorating sickle cell disease