title: Functional properties of the newly observed (G)γ-chain fetal hemoglobin variant Hb F-Monserrato-Sassari (HBG2:c.280T>C) or [(G)γ93 (F9) Cys→Arg].
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 (G)γ 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.
  
  
  CONCLUSIONS
  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 (G)γ 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.
authors.affiliation: Dipartimento di Scienze Applicate ai Biosistemi, Università di Cagliari, Italy.
authors.forename: Mariagiuseppina
authors.initials: M
authors.lastname: Pellegrini
authors.forename: Barbara
authors.initials: B
authors.lastname: Manconi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Olianas
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Sanna
authors.forename: Claudia
authors.initials: C
authors.lastname: Meloni
authors.forename: Monica
authors.initials: M
authors.lastname: Pirastru
authors.forename: Paolo
authors.initials: P
authors.lastname: Mereu
authors.forename: Giovanni
authors.initials: G
authors.lastname: Leoni
authors.forename: Bruno
authors.initials: B
authors.lastname: Masala
authors.forename: Laura
authors.initials: L
authors.lastname: Manca
mesh_terms: D001120:Arginine / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D003545:Cysteine / Q000737:chemistry; D005319:Fetal Hemoglobin / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D006801:Humans; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D005319:Fetal Hemoglobin; D001120:Arginine; D003545:Cysteine