Two novel unstable hemoglobin variants due to in-frame deletions of key amino acids in the β-globin chain

SCHEPS, KAREN G.; HASENAHUER, MARCIA ANAHÍ; PARISI, GUSTAVO; TARGOVNIK, HÉCTOR M.; GARCÍA, ELIANA; VEBER, ERNESTO SAMUEL; CRISP, RENÉE; ELENA, GRACIELA; VARELA, VIVIANA; FORNASARI, MARÍA SILVINA

EUROPEAN JOURNAL OF HAEMATOLOGY

WILEY-BLACKWELL PUBLISHING, INC

Año: 2018 vol. 100 p. 529 - 535

0902-4441

Hemoglobinopathies are the most common autosomal recessive disorders and are mostly inherited in a recessive manner. However, certain mutations can affect the globin chain stability, leading to dominant forms of thalassemia. The aim of this work was the molecular and structural characterization of two heterozygous in-frame deletions, leading to beta-globin variants in pediatric patients in Argentina. The HBB gene of the probands and their parents was sequenced, and other markers of globin chain imbalance were analyzed. Several structural analyses were performed and the effect of the mutations on the globin chain stability was analyzed. In Hb JC-Paz, HBB:c.29_37delCTGCCGTTA (p.Ala10_Thr12del), detected in an Argentinean boy, one α-helix turn is expected to be lost. In Hb Tavapy, HBB:c.182_187delTGAAGG (p.Val60_Lys61del), the deleted residues are close to distal histidine (His63) in the heme pocket. Both mutations are predicted to have a destabilizing effect. The development of computational structural models and bioinformatics algorithms is expected to become a useful tool to understand the impact of the mutations leading to dominant thalassemia.