Haemoglobin Biology and Disorders

Short version. Adult haemoglobin (HbA) is α₂β₂; HbA₂ is α₂δ₂; foetal haemoglobin (HbF) is α₂γ₂. The α-globin genes (HBA1, HBA2) cluster on 16p13.3; the β-like genes (HBB, HBD, HBG1, HBG2, HBE1) cluster on 11p15.5. Sickle cell anaemia is the textbook single-base disease — HBB:c.20A>T producing β6 Glu→Val. The thalassaemias are quantitative deficits in α- or β-chain synthesis; α-thalassaemia is dominated by deletion alleles, β-thalassaemia by ~200 point and small-indel mutations. The page closes on the developmental haemoglobin switch, the BCL11A axis, and the published gene-therapy literature for sickle cell and β-thalassaemia.

The haemoglobin tetramer

Mammalian haemoglobin is a heterotetramer of two α-like and two β-like globin chains, each binding a haem prosthetic group. The combinations that matter clinically:

HbA — α₂β₂. The dominant adult haemoglobin, ~96% of the total in healthy adults.
HbA₂ — α₂δ₂. ~2–3% in healthy adults; raised in β-thalassaemia trait, where it is the standard quantitative diagnostic marker on HPLC.
HbF — α₂γ₂. The dominant haemoglobin from week 8 of gestation through to ~6 months postnatal; <1% in adults except in HbF persistence (HPFH), β-thalassaemia, and sickle cell disease where it has a partially protective role.
HbS, HbC, HbE, HbD — structural β-chain variants, see below.

The α-globin and β-globin chains are related by deep homology — both descend from a single ancestral globin gene. The 3D structure of haemoglobin and the cooperative oxygen binding curve are textbook material; the canonical Perutz papers from the 1960s and the entries at the RCSB Protein Data Bank remain the visual references.

The HBB and HBA loci

The two globin gene clusters sit on different chromosomes and have related but distinct architectures. The α-globin cluster on 16p13.3 contains, in 5′–3′ order, HBZ (zeta), HBA2, HBA1, plus the embryonic / pseudogene members. The β-globin cluster on 11p15.5 contains, in 5′–3′ order, HBE1 (epsilon, embryonic), HBG2 (Gγ), HBG1 (Aγ), HBD (delta, adult, low), HBB (beta, adult, dominant). Expression is regulated developmentally by the upstream Locus Control Region (LCR) and the local cis-elements.

HGNC links: HBB, HBA1, HBA2. OMIM: HBB 141900, HBA1 141800.

The haemoglobin switch

Haemoglobin composition changes twice during development. The first switch is from embryonic Hb (Hb Gower-1, Hb Gower-2, Hb Portland) at ~6 weeks gestation to foetal HbF (α₂γ₂); the second is the gradual γ→β switch around birth, which completes by approximately 6 months postnatal. The molecular basis of the γ→β switch is the developmental upregulation of the BCL11A repressor, which binds the γ-globin promoters and represses transcription, allowing β-globin to dominate. Disrupting BCL11A binding — whether by mutation in the BCL11A erythroid enhancer, or by editing it — derepresses γ-globin and raises HbF.

Hereditary persistence of foetal haemoglobin (HPFH) is the classic experiment of nature: individuals with non-deletional HPFH variants in the γ-globin promoters or with deletions of the β-globin LCR continue to express HbF into adulthood. Because HbF dilutes HbS in sickle cell disease and partially compensates for absent β-chain in β-thalassaemia, HPFH carriers who inherit a sickle or β-thal allele in trans have milder disease. This observation — that more HbF is good in β-haemoglobinopathies — is the basis for the γ-globin reactivation strategies pursued by hydroxycarbamide and, more recently, by gene editing.

Sickle cell anaemia

The first disease shown to be molecular. Pauling et al. 1949 (Science 110:543) separated sickle cell haemoglobin from normal haemoglobin by electrophoresis. Ingram 1957 (Nature 180:326) showed by tryptic peptide fingerprinting that the difference was a single amino acid substitution at position 6 of the β chain — glutamic acid replaced by valine. In modern HGVS notation: HBB:c.20A>T (p.Glu6Val), rs334. ClinVar entry: VCV000015333.

The pathophysiology hinges on the hydrophobic valine. Under deoxygenation, HbS molecules polymerise into rigid 14-stranded fibres that distort the red cell into a sickle shape, occlude the microvasculature, and shorten erythrocyte lifespan. Homozygotes (HbSS) have classic sickle cell anaemia; HbS/β-thal compound heterozygotes have a sickle-thalassaemia phenotype that varies with the residual β-chain output of the β-thal allele; HbS/HbC compound heterozygotes have the milder HbSC disease.

The high allele frequency of HbS in sub-Saharan Africa, parts of the Mediterranean, the Arabian peninsula, and the Indian subcontinent is explained by balancing selection against Plasmodium falciparum malaria. Allison 1954 (BMJ 1:290) showed that HbAS heterozygotes had a survival advantage in malaria-endemic areas. Five different HbS-bearing β-globin haplotypes (Senegal, Benin, Bantu / Central African Republic, Cameroon, Arab–Indian) have been documented, indicating multiple independent origins of the c.20A>T mutation.

HbC, HbE, and HbD

Three other clinically relevant β-chain structural variants:

HbC (β6 Glu→Lys, HBB:c.19G>A) — common in West Africa. HbCC homozygotes have mild haemolytic anaemia; HbSC compound heterozygotes have a moderate sickle-disease phenotype.
HbE (β26 Glu→Lys, HBB:c.79G>A) — the most common abnormal haemoglobin in Southeast Asia. HbE acts as a mild β-thalassaemia allele because the mutation activates a cryptic splice site, reducing β-chain output. HbE/β-thal compound heterozygotes are the dominant cause of severe transfusion-dependent thalassaemia in much of Southeast Asia.
HbD-Punjab (β121 Glu→Gln) — found across the Indian subcontinent. HbDD is mild; HbSD-Punjab compound heterozygotes have a sickle-disease phenotype.

α-thalassaemia

α-thalassaemia is overwhelmingly a disease of α-globin gene deletions. Each diploid individual carries four α-globin genes: HBA1 and HBA2 on each copy of chromosome 16 (αα/αα). Deletions of one or two α genes are by far the commonest mechanism. The principal deletional alleles:

-α^3.7 and -α^4.2 — common single-α deletions in African and Mediterranean populations. -α/αα is the silent carrier state.
--^SEA, --^FIL, --^THAI, --^MED, -(α)^20.5 — cis double-α deletions (both α genes on one chromosome 16 deleted). The Southeast Asian (--^SEA) and Mediterranean (--^MED) deletions are most clinically relevant because of the carrier frequency in their populations.

The phenotypic series:

-α/αα (one of four α genes deleted): silent carrier; haematology normal or near-normal.
-α/-α or --/αα (two of four deleted): α-thalassaemia trait; mild microcytic hypochromic picture, normal HbA₂.
--/-α (three of four deleted): HbH disease; moderate haemolytic anaemia with HbH (β₄) inclusions.
--/-- (all four deleted): Hb Bart's hydrops fetalis (γ₄). Almost always lethal in utero or shortly after birth without intervention; the clinical literature is reviewed in Vichinsky 2009 (Hemoglobin / Hematology Am Soc Hematol Educ Program).

The two-gene α-thalassaemia genotype is important for genetic counselling because cis (--/αα, both α genes on one chromosome) and trans (-α/-α, one α gene deleted on each chromosome 16) configurations have very different reproductive consequences: the cis configuration in both partners can produce hydrops, the trans configuration in both partners cannot. Distinguishing them requires molecular genotyping; the haematological indices alone cannot do it. The case for documenting α-thalassaemia configuration in a structured pedigree, ahead of any reproductive decision-making, is reviewed in our for reproductive medicine page.

β-thalassaemia

β-thalassaemia is mostly a disease of point mutations and small indels in the HBB gene and its regulatory regions. More than 200 different mutations have been catalogued (see the HbVar database); the GeneReviews chapter on β-thalassaemia (Origa 2017) is the canonical clinical reference. Mutations are grouped by their effect on β-chain output:

β⁰ alleles abolish β-chain output. Examples: nonsense mutations such as IVS-I-1 (G→A), c.118C>T (CD39 nonsense), c.92+1G>A.
β⁺ alleles allow reduced β-chain output. Examples: IVS-I-110 G→A, IVS-I-6 T→C, the −28 A→G promoter mutation.

The phenotypic series, traditionally:

β-thalassaemia trait (heterozygote): asymptomatic or mild microcytic hypochromic picture; raised HbA₂ on HPLC is the standard marker.
β-thalassaemia intermedia: a clinical category, not a genotype, covering symptomatic patients who do not require regular transfusion. Common genotypes include β⁺/β⁺ with milder alleles, and β/β with co-inherited α-thalassaemia or HPFH that mitigates chain imbalance.
β-thalassaemia major: severe transfusion-dependent disease, classically β⁰/β⁰. Iron overload from chronic transfusion is the dominant late complication.

Geographic distribution mirrors historical malaria endemism. β-thalassaemia is common in Mediterranean populations (Greece, Italy, Cyprus, Sardinia), the Middle East, North Africa, the Indian subcontinent, and Southeast Asia. The HbE/β-thal compound heterozygote dominates the disease burden in much of Southeast Asia. Weatherall & Clegg's The Thalassaemia Syndromes (4th edition, 2001) is the deep textbook reference; Vichinsky 2009 covers the global epidemiology.

HbF persistence and γ-globin reactivation

Reactivating γ-globin is therapeutically attractive because HbF dilutes HbS and substitutes for absent β-chain. Two strategies have been pursued:

Pharmacological. Hydroxycarbamide / hydroxyurea raises HbF through poorly-understood erythroid stress mechanisms; the published evidence base in sickle cell disease is large, and the drug is generic.
Gene editing. The CTX001 / exa-cel approach, developed by Vertex Pharmaceuticals and CRISPR Therapeutics, uses CRISPR-Cas9 to disrupt the BCL11A erythroid enhancer in autologous CD34+ haematopoietic stem cells, derepressing γ-globin in the patient's own erythroid progeny. Frangoul et al. 2021 (NEJM 384:252) reported the first treated patients — one with transfusion-dependent β-thalassaemia, one with severe sickle cell disease — both with high stable HbF and clinical improvement at the time of publication.

The product (now branded Casgevy) received conditional UK MHRA approval on 16 November 2023 and US FDA approval on 8 December 2023 for severe sickle cell disease in patients aged 12 and over, followed shortly by approval for transfusion-dependent β-thalassaemia. We cite the literature and the regulatory record neutrally; treatment decisions are made by clinicians with their patients. Evagene is an educational platform.

Pedigree-level reading

The haemoglobinopathies are textbook autosomal recessive disorders, with a few quirks. Common pedigree patterns:

Sickle cell anaemia: two carrier parents, ~25% of offspring affected, with pedigrees often spanning consanguineous unions or families from sub-Saharan, Mediterranean, or South Asian heritage.
β-thalassaemia major: same recessive pattern; carrier-screening programmes in Cyprus, Sardinia, and Iran have reshaped the pedigree distribution by reducing affected births.
HbE/β-thalassaemia: compound heterozygote pedigrees with one HbE carrier parent and one β-thal carrier parent.
α-thalassaemia hydrops: two parents both carrying cis double-α deletions (--/αα).
Mild dominant β-thalassaemia: rare unstable haemoglobin alleles (e.g. Hb Geneva) can produce a dominantly transmitted thalassaemia phenotype.

Drawing one of these pedigrees in Evagene's pedigree drawing tool using a fictional family is a standard teaching exercise. The Mendelian inheritance calculator can illustrate carrier and offspring probabilities; see Mendelian inheritance calculator. Outputs are illustrative for teaching, not clinical.

Key references

Pauling L, Itano HA, Singer SJ, Wells IC. Sickle cell anemia, a molecular disease. Science 1949; 110:543–548. PMID 15395398.
Ingram VM. Gene mutations in human haemoglobin. Nature 1957; 180:326–328. PMID 13464827.
Allison AC. Protection afforded by sickle-cell trait against subtertian malarial infection. BMJ 1954; 1:290. PMID 13115700.
Weatherall DJ, Clegg JB. The Thalassaemia Syndromes. 4th ed. Oxford: Blackwell Science; 2001.
Origa R. β-Thalassemia. In: GeneReviews. Seattle: University of Washington; 2017 (last update 2024). NBK1426.
Vichinsky EP. Alpha thalassemia major — new mutations, intrauterine management, and outcomes. Hematology Am Soc Hematol Educ Program 2009; 35–41. PMID 19797991.
Frangoul H, Altshuler D, Cappellini MD, et al. CRISPR-Cas9 gene editing for sickle cell disease and β-thalassemia. NEJM 2021; 384:252–260. PMID 33283989.
HbVar database of haemoglobin variants and thalassaemia mutations. globin.bx.psu.edu/hbvar.
OMIM: HBB 141900; HBA1 141800; sickle cell anaemia 603903; β-thalassaemia 613985.

Frequently asked questions

What is the molecular basis of sickle cell anaemia?

A single base substitution in HBB: c.20A>T, which replaces glutamic acid at position 6 of the β chain with valine. The substitution causes deoxygenated HbS to polymerise. Identified by Ingram in 1957 and named "the first molecular disease" by Pauling et al. in 1949.

Why is α-thalassaemia mostly a deletion disorder?

The two α-globin genes (HBA1, HBA2) are tandemly duplicated on 16p13.3 and embedded in highly homologous repeat regions, which makes them prone to non-allelic homologous recombination and hence to deletion. Most α-thalassaemia alleles in the global population are deletional.

Why does the cis vs trans configuration of α-thalassaemia matter?

Two parents both carrying cis double-α deletions (--/αα) can produce a foetus with all four α genes deleted (--/--), which is Hb Bart's hydrops fetalis. Two parents both carrying trans single-α deletions (-α/-α) cannot. The haematological indices alone cannot distinguish the two states; molecular genotyping is required.

Why does HbF reactivation help in sickle cell and β-thalassaemia?

In sickle cell disease, HbF dilutes HbS and inhibits its polymerisation. In β-thalassaemia, γ chains pair with surplus α chains, reducing the chain imbalance that drives ineffective erythropoiesis. Hereditary persistence of foetal haemoglobin (HPFH) co-inherited with a β-haemoglobinopathy ameliorates the phenotype, which is the natural-experiment basis for therapeutic γ-globin reactivation.

Is Casgevy / exa-cel a recommendation?

No. We cite Frangoul et al. 2021 (NEJM 384:252) and the November 2023 MHRA / December 2023 FDA approvals neutrally as published research and regulatory record. Evagene is an educational and research platform and does not make treatment recommendations.

Where does pedigree drawing fit in haemoglobinopathy teaching?

Drawing fictional carrier-couple pedigrees for sickle cell, β-thalassaemia, HbE/β-thal, and α-thalassaemia hydrops in NSGC notation is the standard exercise for autosomal-recessive teaching. Evagene's pedigree drawing tool draws these in the browser and the Mendelian inheritance calculator covers the offspring probabilities.