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Ancestral β-globin gene haplotypes modify β-thalassemia severity in a mouse model

Year: 2024

Type: article

Abstract: Mutations in the HBB gene cause β-thalassemia by inhibiting the production of the β-globin subunit of adult hemoglobin (HbA, α2β2). 1 Consequently, excess free α-globin forms cytotoxic precipitates that cause maturation delay and apoptosis of erythroid precursors (ineffective erythropoiesis [IE]) and shortened lifespan of circulating red blood cells (RBC) (hemolysis).The severity of β-thalassemia varies according to the causal HBB mutation and modifier alleles that influence the ratio of α-globin to β-like globins (mainly βand γ-), which form HbA or fetal hemoglobin (α2γ2), respectively.Patients with transfusion-dependent (TD) β-thalassemia, also called β-thalassemia major, express little or no β-like globin and require regular RBC transfusions.Patients with non-transfusion-dependent (NTD) β-thalassemia, also called β-thalassemia intermedia, express residual β-globin and/or γ-globin and require transfusions sporadically.Both TD β-thalassemia and NTD β-thalassemia are common disorders that cause substantial morbidity and premature mortality.Mouse models for β-thalassemia are helpful for elucidating disease pathophysiology and developing new therapies.2 These models were created by generating targeted mutations in the mouse β-globin (Hbb) genes.While humans have a single HBB gene on each chromosome, mice express β-globin from 2 tandem, ancestrally duplicated Hbb genes.[3][4][5] Common inbred strains of mice used for laboratory research harbor one of 2 different Hbb haplotypes, termed single and diffuse (supplemental Figure 1A).The Hbb single haplotype, normally found in C57BL/6 mice, contains Hbb-bs and Hbb-bt, which encode identical β-globin proteins.The diffuse haplotype, found in 129 and BALB/c strains, contains Hbb-b1 and Hbb-b2, which encode proteins that differ from each other and from β-globin single (supplemental Figure 1B-C).The Hbb-b1 and Hbb-b2 genes are also referred to as Hbb-major (β maj ) and Hbb-minor (β min ) because they generate ~80% and 20% of RBC β-globin protein, respectively.6

Source: Blood Advances

DOI: 10.1182/bloodadvances.2024012681