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Functional properties of the newly observed Gγ-chain fetal hemoglobin variant Hb F-Monserrato-Sassari (HBG2:c.280T > C) or [Gγ93 (F9) Cys → Arg]

Pellegrini, Mariagiuseppina and Manconi, Barbara and Olianas, Alessandra and Sanna, Maria Teresa and Meloni, Claudia and Pirastru, Monica and Mereu, Paolo and Leoni, Giovanni Giuseppe and Masala, Bruno Lucio and Manca, Laura (2011) Functional properties of the newly observed Gγ-chain fetal hemoglobin variant Hb F-Monserrato-Sassari (HBG2:c.280T > C) or [Gγ93 (F9) Cys → Arg]. Biochimica et Biophysica Acta. General Subjects, Vol. 1810 (12), p. 1272-1277. ISSN 0304-4165. Article.

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DOI: 10.1016/j.bbagen.2011.06.007

Abstract

Background
HbF-Monserrato-Sassari is a newly discovered abnormal fetal hemoglobin observed in an apparently normal newborn baby during a hemoglobinopathies survey at birth in North Sardinian population.
Methods
Electrophoretic analysis of the cord blood lysate evidenced for an abnormal tetramer due to a mutated fetal globin chain. Electrospray ionisation-mass spectrometry and gene sequencing were used to identify the mutation. Oxygen binding ability of the variant Hb was determined.
Results
Sequencing of the γ globin genes revealed the TGT → CGT transition at codon 93 in one of the two Gγ genes, which leads to the Arg for Cys amino acid replacement at position 9 of the F α-helix. The amino acid substitution was confirmed by mass spectrometric analysis of the globin chains. Since modifications or substitutions at position β93 are known to affect the arrangement of a salt bridge at the α1β2 sliding contacts that are crucial for subunit cooperativity, the functional properties of the variant were studied to evaluate the effect of the replacement at the same position in the γ globin chain. With respect to normal HbF, the variant showed a significant increase in oxygen affinity and a slight decrease of both Bohr effect and cooperativity.
General significance
Result indicates a key role of the Cys γ93 residue for subunit cooperativity in the T → R transition of the HbF tetramer. Substitutions at the F9 position of the Gγ globin may result in stabilization of the high affinity R-state of the Hb tetramer. Because of the loss of Cys γ93 residue, this variant is considered to be potentially compromised in nitric oxide transport.

Item Type:Article
ID Code:6364
Status:Published
Refereed:Yes
Uncontrolled Keywords:HbF variant, Gγ globin gene, gene sequencing, α1γ2 interface, oxygen affinity, NO transport
Subjects:Area 05 - Scienze biologiche > BIO/10 Biochimica
Divisions:001 Università di Sassari > 02 Centri > Centro di eccellenza interdisc. sviluppo ricerca biotecnologica e studio biodiversità della Sardegna e dell'area mediterranea
001 Università di Sassari > 01 Dipartimenti > Scienze fisiologiche, biochimiche e cellulari
Publisher:Elsevier
ISSN:0304-4165
Copyright Holders:© 2011 Elsevier
Deposited On:22 Aug 2011 10:13

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