HB Washtenaw [βT11(A8)VAL-PHE]: An Electrophoretically Silent, Unstable, Low Oxygen Affinity Variant Associated with Anemia and Chronic Cyanosis

Abstract

Hb Washtenaw [beta 11(A8)Val-->Phe] is a new, low oxygen affinity variant with a previously undescribed substitution, identified in seven members over three generations of a Hungarian-American family. The hemoglobin is mildly unstable and the family members studied are clinically asymptomatic but mildly cyanotic, and some exhibit mild anemia. The index case had severe pulmonary hypertension and some of the family members had increased pulmonary vascular resistance on echocardiography. An association between the inheritance of this abnormal hemoglobin and the pathogenesis of primary pulmonary hypertension is suggested but the mechanism is unclear.

Pleiotropic effects of intravascular haemolysis on vascular homeostasis

“…Although SCD and thalassaemia could be, in a manner of speaking, considered unstable haemoglobin disorders, this label is usually reserved for other mutations of the globin subunits that produce no other readily observed feature than haemolytic anaemia. PH has been reported in patients with several unstable haemoglobinopathies (Honig et al , 1989; Krishnan et al , 1994; Lode et al , 2007). The same is true for priapism (Thuret et al , 1996; Gyan et al , 2001; Andrieu et al , 2003).…”

Priapism following splenectomy in an unstable hemoglobin: Hemoglobin Olmsted β141 (H19) Leu→Arg

“…The original patient with Hb Olmsted died of a chronic pulmonary disease with pulmonary hypertension at age 36 years [7]. In our case, a priapism occurred 8 years in cases of unstable hemoglobin, splenectomy probably increases RBC rigidity and adherence to endothelial cells by inducing reticulocytosis and cells containing Heinz or Howell-Jolly bodies.…”

δ-Thalassemic phenotype due to two “novel” δ-globin gene mutations: CD11[GTC → GGC (A8)-HbA2-pylos] and CD 85 [TTT → TCT (F1)-HbA2-etolia]

“…It is known that the residues lining the heme pocket form a kind of "hydrophobic basket," thus preventing the oxidation of the heme iron to its ferric state. The importance of Val in this position is underscored by the fact that it is conserved through almost all mammalians Ä-globin gene (except shark and chicken), and is present even in midge larvae and legume Hb (Krishnan et al, 1994). Isoleucine, also a hydrophobic amino acid, exists normally at cd11 of the human ò-and Ö-globin gene; similar changes in cases of Ä-variants as Hb-Washtenaw (cd11,ValÃPhe) or HbHamilton (cd11,ValÃIleu) result either in mild instability (Krishnan et al, 1994) or in a "silent" variant (Wong et al, 1984).…”

“…The importance of Val in this position is underscored by the fact that it is conserved through almost all mammalians Ä-globin gene (except shark and chicken), and is present even in midge larvae and legume Hb (Krishnan et al, 1994). Isoleucine, also a hydrophobic amino acid, exists normally at cd11 of the human ò-and Ö-globin gene; similar changes in cases of Ä-variants as Hb-Washtenaw (cd11,ValÃPhe) or HbHamilton (cd11,ValÃIleu) result either in mild instability (Krishnan et al, 1994) or in a "silent" variant (Wong et al, 1984). By contrast, the substitution of Val to Asp in the Ä-globin gene (Hb-Windsor) (Gilbert et al, 1989) reduces the hydrophobicity of the "basket," resulting in an unstable molecule, "Hb H"-like inclusions, and severe hemolysis.…”