Hemoglobin E (HbE) results from a substitution at codon 26 of the beta-globin gene (Glu→Lys). At the molecular level, this mutation is significant because it:

• A Directly destabilizes the hemoglobin tetramer, causing intravascular hemolysis
• B Eliminates the 2,3-DPG binding site, increasing oxygen affinity
• C Creates an aberrant splice site, reducing normal beta-globin mRNA production ✓
• D Causes polymerization under deoxygenated conditions similar to HbS

Explanation

The codon 26 (GAG→AAG, Glu→Lys) substitution of HbE also creates a cryptic splice site in exon 1 of the beta-globin gene, activating alternative splicing that reduces normal beta-globin mRNA output; HbE behaves as both a structural variant and a mild beta-thalassemia allele. Compound heterozygosity of HbE/beta-thalassemia produces a moderately severe thalassemia syndrome. HbE does not polymerize under hypoxia (that is specific to HbS), does not cause intravascular hemolysis, and does not alter 2,3-DPG binding.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

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Written and medically reviewed by the StethoPrep medical team.