title: Interaction of 2 amino acid substitutions within the same beta chain of human hemoglobin: the examples of Hb Corbeil and Hb Villeparisis.
abstract: Only 16 hemoglobin (Hb) variants carrying 2 point mutations within the same polypeptide chain have been identified up to now. Two of those are reported in this paper. In Hb Villeparisis, the beta 77 (EF1) His-->Tyr mutation is identical to that of Hb Fukuyama while the other mutation, beta 80 (EF4) Asn-->Ser, has not yet been described. These 2 abnormalities are located almost within interacting distance. They lead to decreased oxygen affinity and, according to molecular simulations, to a remodeling of the surface of the molecule. Hb Corbeil associates 2 substitutions, that of Hb E [beta 26 (B8) Glu-->Lys], and of Hb Sherwood Forest [beta 104 (G6) Arg-->Thr], which are far from one another. The resulting properties consist only in the additive effects of both abnormalities. Hb Corbeil is, thus, a thalassemic Hb, like Hb E, and a molecule having altered oxygen binding properties, characterized by decreased heterotropic effects, similar to those of Hb Sherwood Forest. The simultaneous presence of more than 1 structural abnormality leads to a large spectrum of possible consequences on the function of the molecule, from local effects to a perturbation of intermolecular interactions. The genetic mechanism resulting in Hb with more than 1 point mutation is discussed: in some cases it is very likely that the second mutation arose on a chromosome already carrying a point mutation, in contrast a single mutational event involving a micro gene conversion has been proposed in other cases.
authors.affiliation: INSERM U. 91, hôpital Henri-Mondor, Créteil, France.
authors.forename: H
authors.initials: H
authors.lastname: Wajcman
authors.forename: J
authors.initials: J
authors.lastname: Kister
authors.forename: D
authors.initials: D
authors.lastname: Promé
authors.forename: Y
authors.initials: Y
authors.lastname: Blouquit
authors.forename: C
authors.initials: C
authors.lastname: Préhu
authors.forename: C
authors.initials: C
authors.lastname: Poyart
authors.forename: F
authors.initials: F
authors.lastname: Galactéros
mesh_terms: D000495:Allosteric Site; D004586:Electrophoresis; D006455:Hemoglobins, Abnormal / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D008958:Models, Molecular; D010100:Oxygen / Q000378:metabolism; D017354:Point Mutation
chemical_list: D006455:Hemoglobins, Abnormal; D010100:Oxygen