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Identification of a Novel Mutation in the β-Globin Gene 3′ Untranslated Region (HBB: c.*+118A > G) in Spain

Abstract The 3′ untranslated region (3′UTR) region is well known to be associated with mRNA stability because of its associations with 3′ end processing, polyadenylation and mRNA capping. Mutations located in this area cause a β-thalassemia (β-thal) phenotype compatible with β+-thal. Two brothers, 49- and 41-years-old, were diagnosed with β-thal intermedia (β-TI) at 2 years of age. The β-globin gene from the promoter region to the 3′UTR was sequenced and both brothers were diagnosed to be compound heterozygotes for the 3′UTR +1592 (A > G) (HBB: c.*+118A > G) and codon 39 (C > T) (HBB: c.118C > T) mutations. Their mother was a carrier of the nonsense codon 39 mutation and her hematological data suggested β-thal trait; their father was a carrier of the 3′UTR +1592 mutation, though he did not have hematological parameters associated with β-thal. The adenine at position +1592 or +118 bases downstream of the termination codon is highly conserved among primates and placental mammals, as it is located between the polyadenylation A signal (PAS) and the polyadenylation A cleavage (PAC) sites. Given its location, it is likely that this mutation would interfere with mRNA maturation; however, the clinical data of the heterozygous carriers show virtually no significant alterations. Therefore, we suggest that the impact on cleavage-stimulation factor (CstF) recognition of the mRNA sequence would be minimal and not significantly alter polyadenylation. Although the mechanism is not known, and because the carrier has no β-thal minor, the mRNA is stable enough that the synthesis of the β-globin chain is unaffected.