A novel β-globin structural mutant, Hb Brescia (β114 Leu-Pro), causing a severe β-thalassemia intermedia phenotype

This study describes a patient with a thalassemia intermedia‐like phenotype in whom β‐globin gene sequencing detected a novel abnormal hemoglobin (Hb) due to a T‐C substitution at codon 114 of the β‐globin gene arising as a de novo mutation. The abnormal variant was designated Hb Brescia after the place of birth of the propositus. Normal sequences were detected at the in trans β‐globin locus. In addition, α‐globin gene analysis detected a triple α‐globin locus which was inherited from the father. The T‐C change at position 114 of the β‐globin gene results in a leucine to proline substitution (Leu‐Pro) in the G‐helix. The resulting Hb tetramer is highly unstable and precipitates forming inclusion bodies in the peripheral red blood cells. Moreover, the Leu‐Pro substitution interferes negatively with the four α1β1 contact points of the G‐helix most likely adversely affecting the αβ dimer formation. The very severe phenotype presented by our patient is unusual in a heterozygote for an unstable Hb variant and may be explained by the coinheriance of the triple α‐globin locus. © 1992 Wiley‐Liss, Inc.