title: α-Hemoglobin stabilizing protein: a modulating factor in thalassemias?
abstract: α-Hemoglobin stabilizing protein (AHSP) is a small protein of 102 residues induced by GATA-1, Oct-1- and EKLF. It is synthesized at a high level in the red blood cell precursors and acts as a chaperone protecting the α-hemoglobin (α-Hb) chains against precipitation. α-Hemoglobin stabilizing protein forms a heterodimer complex with α-Hb, then displaying modified oxygen binding kinetics. In the absence of AHSP, α-Hb oxidizes and precipitates within the erythrocyte precursors of bone marrow leading to apoptosis and defective erythropoiesis. Several α-Hb variants with a structural abnormality, frequently located in the contact area between α-Hb and AHSP, exhibit instability and a thalassemia-like syndrome when they are associated with another α-thalassemia (α-thal) determinant. We suggest that this disorder could result from a disturbed interaction between the abnormal α-Hb chains and AHSP. Hb Groene Hart (Pro119>Ser) was one of the first examples in which we observed this abnormality. We later verified this mechanism in a list of several variants, now considered as being nondeletional α-thalassemias. Conversely, it was hypothesized from studies on knock-out mice, that a defect affecting AHSP could cause a thalassemia-like syndrome. This was supported in man by studies showing that a decreased expression of AHSP linked to specific genetic clades could act as a modulating factor in some thalassemia phenotypes. It was also supported by our observation of a family from Southeast Asia, in which a child homozygous for an AHSP mutant (Val56>Gly) displayed, in his first year of life, a moderate thalassemia syndrome. This mutant AHSP was expressed in vitro and demonstrated by biochemical and biophysical studies to display a clear defective interaction with α-Hb, which could support the hypothesis that the reb blood cell (RBC) disorders of the child resulted from this abnormality. It therefore appears that AHSP is a factor with a key role in the formation of Hb tetramers and that structural abnormalities, either on the α-Hb or on the AHSP, may act as a thalassemia modulating factor.
authors.affiliation: Inserm U955, IMRB, Université Paris Est, 94010 Créteil, France. Henri.Wajcman@inserm.fr
authors.forename: Henri
authors.initials: H
authors.lastname: Wajcman
authors.forename: Corinne
authors.initials: C
authors.lastname: Vasseur
authors.forename: Serge
authors.initials: S
authors.lastname: Pissard
authors.forename: Veronique
authors.initials: V
authors.lastname: Baudin-Creuza
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D010641:Phenotype; D011485:Protein Binding / Q000502:physiology; D013789:Thalassemia / Q000235:genetics / Q000378:metabolism*; D055542:alpha-Globins / Q000378:metabolism*
chemical_list: C468768:AHSP protein, human; D001798:Blood Proteins; D018832:Molecular Chaperones; D055542:alpha-Globins