Hb Monza: A novel extensive HBB duplication with preserved α-β subunit interaction and unstable hemoglobin phenotype.

Autor:	Civettini I; Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; Hematology Department, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy. Electronic address: civettini.ivan@hsr.it., Zappaterra A; Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; Hematology Department, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy., Corti P; Pediatrics, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy., Messina A; Transfusion Medicine, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy., Aroldi A; Hematology Department, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy., Biondi A; Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; Pediatrics, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy., Cavalca F; Hematology Department, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy., Crippa V; Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy., Crosti F; Genetic Medicine, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy., Ferrari GM; Pediatrics, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy., Malighetti F; Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy., Mologni L; Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy., Piperno A; Centro Ricerca Tettamanti, Monza, Italy., Ramazzotti D; Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy., Scollo C; Transfusion Medicine, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy., Zambon A; Department of Chemical and Geological Science, Modena and Reggio Emilia University, Modena, Italy., Rossi F; Transfusion Medicine, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy., Gambacorti-Passerini C; Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; Hematology Department, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy.
Jazyk:	angličtina
Zdroj:	Med (New York, N.Y.) [Med] 2024 Dec 14. Date of Electronic Publication: 2024 Dec 14.
DOI:	10.1016/j.medj.2024.11.007
Abstrakt:	Background: Unstable hemoglobins are caused by single amino acid substitutions in the HBB gene, often affecting key histidine residues, leading to protein destabilization and hemolytic crises. In contrast, long HBB variants, exceeding 20 bp, are rare and associated with a β-thalassemia phenotype due to disrupted α-β chain interactions. We describe a family wherein four of six members carry a novel 23-amino-acid in-frame duplication of HBB (c.176_244dup), named hemoglobin (Hb) Monza. Despite its length, this duplication manifests as an unstable hemoglobin variant rather than a β-thalassemia phenotype. Methods: A static 3D model of the Hb Monza β chain was generated using AlphaFold and SWISS-MODEL. Molecular dynamics (MD) simulations were performed with the Generalized Born implicit solvent model. After energy minimization and heating to 311 K (38°C), a 40 ns production run was conducted. Findings: 3D modeling of Hb Monza revealed minimal structural changes in the Hb β chain, particularly in the key histidine residues and their interaction with the iron atom. Additionally, the static 3D model showed a preserved α-β interaction, explaining the absence of a β-thalassemia clinical phenotype. MD simulations under thermal stress revealed a notable increase in root-mean-square deviation compared to the wild-type β subunit, along with a loss of contacts with the heme, explaining the hemolytic crises during febrile episodes. Conclusion: Despite the long duplication in HBB, Hb Monza retains functional α-β interaction while demonstrating instability under stressful conditions. This unique variant presents with an unstable Hb phenotype rather than a β-thalassemia phenotype. Funding: No financial funding was received. Competing Interests: Declaration of interests The authors declare no competing financial interests. (Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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