Certain structural Hb variants are characterized by the presence of a biosynthetic defect as well as abnormal structure. Thalassemic hemoglobinopathies are unusual forms of thalassemia caused by such structural variants.

 Hemoglobin Lepore

 Hb Lepore ( α 2 δ β) is the prototype of a group of hemoglobinopathies characterized by fused globin chains. The chains begin with a normal δ -chain sequence at their N-terminus and end with the normal β -chain sequence at their C-terminus. These hemoglobinopathies arise by unequal or nonhomologous crossover or recombination events that fuse the proximal end of one gene with the distal end of a closely linked structurally homologous gene (Fig. 1). During meiosis, mispairing and crossover of the highly homologous δ- and β-globin genes can occur, resulting in a Lepore chromosome, which contains (in addition to γ-globin genes) only the fused δβ gene, and an anti-Lepore chromosome, which contains the reciprocal fusion product ( δ β), as well as intact δ- and β-globin genes.

Fig1. GENETIC ORIGINS OF HEMOGLOBIN (HB) LEPORE, ANTI-LEPORE HB, AND HB KENYA. (Adapted from Benz EJ Jr. The hemoglobinopathies. In: Kelly WN, DeVita VT, eds. Textbook of Internal Medicine. Philadelphia: JB Lippincott; 1988:1423.)

Lepore globin is synthesized in low amounts, presumably because it is under the control of the δ-globin gene promoter, which normally sustains transcription at only 2.5% the level of the β-globin gene.438 Patients with Hb Lepore have the phenotype of β -thalassemia, distinguished by the added presence of 5% to 15% Hb Lepore. In contrast, the anti-Lepore globin (Miyada) is not associated with a β-thalassemia phenotype because of the presence of an intact and functionally nor mal β-globin gene on the same chromosome.

An analogous but rare variant, Hb Kenya ( α 2[A γ β ]2), arises from nonhomologous crossing over between the ^Aγ- and β-globin genes and is associated with the phenotype of G γ hereditary persistence of fetal Hb. A DNA sequence approximately 600 bases downstream from the β -globin gene acts as a strong enhancer, promoting the erythroid-specific expression of the β -globin genes in adult cells. The fused ^Aγβ gene as well as the linked upstream ^Gγ gene are believed to come under the influence of the enhancer because of its abnormal proximity and thus are expressed at high levels in adult life.

Hemoglobin E

 HbE (α 2 β 2 ^26Glu→Lys) is a common variant (15% to 30% of the population) in Cambodia, Thailand, parts of China, and Vietnam. HbE is very mildly unstable, but this instability does not significantly alter the life span of RBCs. HbE trait resembles very mild β -thalassemia trait. Homozygotes exhibit more microcytosis but are still asymptomatic. Compound heterozygotes for HbE and a β -thalassemia gene (HbE- β -thalassemia) resemble patients with β -thalassemia intermedia or β -thalassemia major. However, some problems such as infection and pulmonary hypertension may occur more commonly in HbE- β -thalassemia than in homozygous β -thalassemia.

The only nucleotide sequence abnormality found in the β E-gene is a base change in codon 26 that causes the amino acid substitution where glutamic acid is replaced by lysine. This mutation, which occurs in a potential cryptic RNA splice region, alters the consensus sequence surrounding a potential GT donor splice site and thus activates the cryptic site. Alternative splicing at this position occurs approximately 40% to 50% of the time, generating a structurally abnormal globin mRNA that cannot be translated appropriately. The other mRNA precursors are spliced at the normal site, generating functionally normal mRNA, which is translated into β E-globin because the mature mRNA retains the base change that encodes lysine at codon 26.

Hemoglobin Constant Spring

 Hb Constant Spring (see Fig. 2) is an elongated α -globin variant resulting from a mutation that alters the normal translation termination codon. Polyribosomes read through the usual translation stop site and incorporate an additional 31 amino acids until another in-phase termination codon is reached within the 3 ′ untranslated sequence. The amount of α cs mRNA is markedly reduced, and αcs globin is synthesized in only minute amounts. Six possible mutations of the normal translation termination codon (UAA ) in α-globin mRNA could result in the generation of a “sense” codon. Of these, five variants have been identified, each having a markedly underproduced abnormal variant, indicating that disruption of nor mal translation termination is in some way associated with abnormal mRNA accumulation, presumably because of instability of the mRNA. The output of α -globin from the α cs allele is only approximately 1% of normal, and the gene is thus rendered α -thalassemic. The α cs allele has been identified only on chromosomes containing a cis-linked functionally normal α -globin gene. Thus, α +-thalassemia trait ( α -/ α csα) and HbH disease–(--/ α csα ) associated with Hb Constant Spring are common, but hydrops fetalis caused by four abnormal α -globin genes cannot occur in association with this variant. Homozygosity for the variant is associated with a relatively mild form of HbH disease.

Fig2. GENETIC ORIGINS OF THE “CLASSIC” α-THALASSEMIA SYNDROMES CAUSED BY GENE DELETIONS IN THE α-GLOBIN GENE CLUSTER. Hemoglobin Constant Spring is an α -globin-chain variant synthesized in such small amounts (1% to 2% of normal) that it has the phenotypic impact of a severe nondeletion α -thalassemia allele; however, the α cs allele is always linked to a functioning α -globin gene, so it has never been associated with hydrops fetalis. CS, Constant Spring; Hb, hemoglobin.

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