Kathleen S. Kubik

Hb DARTMOUTH [α66(E15)Leu → Pro (α2) (CTG → CCG)]: A NOVEL α2-GLOBIN GENE MUTATION ASSOCIATED WITH SEVERE NEONATAL ANEMIA WHEN INHERITED IN TRANS WITH SOUTHEAST ASIAN α-THALASSEMIA-1

We report a novel mutation at α66(E15)Leu → Pro (α2) (CTG → CCG), that we have named Hb Dartmouth for the medical center at which the patients were cared for, in monozygotic twins who also inherited the Southeast Asian α-thalassemia-1 deletion. The mother, of Khmer ancestry, is heterozygous for α-thalassemia-1. The father, who is of Scottish-Irish ancestry, is a silent carrier of the codon 66 mutation. The twins had severe neonatal anemia requiring transfusion.

Hb Chile [β28(B10)Leu→Met]: An unstable hemoglobin associated with chronic methemoglobinemia and sulfonamide or methylene blue-induced hemolytic anemia

Among the causes of life-long cyanosis are congenital methemoglobinemia due to M hemoglobins, congenital methemoglobinemia due to methemoglobin reductase deficiency, a small number of low oxygen affinity hemoglobins, and a small number of unstable hemoglobins that spontaneously form methemoglobin in vivo at an accelerated rate. We report an unstable hemoglobin with these characteristics that was observed in a family of indigenous (native American) origin living near Santiago, Chile. This variant has the substitution beta28(B10)Leu-->Met, unambiguously corresponding to the DNA mutation of CTG-->ATG in beta-globin gene codon 28.

Hb watts [α74(EF3) or α75(EF4)ASP→0]: A shortened α chain variant due to the deletion of three nucleotides in exon 2 of the α2-Globin Gene

We have identified a new, slightly unstable α chain hemoglobin variant, present in a Mexican-American family. Amino acid sequencing and mass spectral analysis of the aberrant peptide (αT-9) of the variant revealed that the aspartic acid is deleted either at position 74 or 75 of one of the α-globin chains. Sequencing of the amplified α2- or α1-globin genes revealed a trinucleotide deletion (GAC) at codon 74 or 74 of the α2 gene. Although the aspartic acid residues of 74 and 75 of the α chain are neither a heme nor an inter chain contact, the slight instability of Hb Watts may be due to disturbance of the central cavity of hemoglobin by the deletion of an aspartic acid residue in the EF helix. Hb Watts is the first example of a trinucleotide deletion in the α2-globin gene.

Hb S/Hb Lepore with mild sickling symptoms : A hemoglobin variant with mostly δ-chain sequences ameliorates sickle-cell disease

Three cases are reported of Hb S/Hb Lepore combination with very mild sickling manifestations. The presence of a nonα‐chain variant with a high proportion of δ chain sequences, including 22 ala, appears to ameliorate sickle‐cell disease. Efforts to increase the proportion of Hb A2 may be beneficial in sickle‐cell disease. Am. J. Hematol. 54:164–165

Three New Hemoglobin Variants with Abnormal Oxygen Affinity: Hb Saratoga Springs [α40(C5)Lys→Asn (α1)], Hb Santa Clara [β97(FG4)His→Asn], and Hb Sparta [β103(G5)Phe→Val]

We report preliminary data for three previously unrecognized, high oxygen affinity hemoglobin (Hb) variants that were initially ascertained because of erythrocytosis in the index cases, or by chromatographic, electrophoretic or isoelectrofocusing (IEF) methods. These variants were also analyzed by DNA sequence analysis, by amino acid sequence analysis of abnormal tryptic peptides, by electrospray ionization-mass spectrophotometry (ESI-MS), or by all these methods, as indicated below for each variant. The methods used have been described previously (1–3). Relative electrophoretic mobilities were calculated as specified by Schneider and Barwick (4). Isoelectrofocusing positions were measured in mm relative to the position of Hb A (5).

Hb RAMPA [α95(G2)Pro→Ser (α2)] IN A FAMILY OF EUROPEAN ANCESTRY: DNA ANALYSIS CONFIRMS THE C CG→T CG MUTATION AT CODON 95 OF THE α2-GLOBIN GENE; CLINICAL AND LABORATORY FEATURES

A 53-year-old asymptomatic male of German ancestry was examined because his half-sister had been found to have Hb S trait, according to a state neonatal screening program for hemoglobinopathies. Further investigations showed that a hemoglobin (Hb) variant was present in five members of this kindred, being the proband, his father, his son, one of his daughters, and his half-sister (Fig. 1). The paternal lineage is believed to be derived from Pomerania, i.e., the Baltic region of northeastern Germany. All heterozygotes were apparently well and hematologically normal or nearly normal (Table 1). In each, the variant was approximately 20% of the total Hb. By peptide chromatography and amino acid sequence analysis, it was shown to be Hb Rampa [a95(G2)Pro!Ser (a2)] rather than Hb S [b6(A3)Glu!Val]. Further studies have now characterized the electrophoretic, isoelectrofocusing (IEF) and chromatographic features; the nature of the Hb Rampa mutation, the stability of Hb Rampa, and its effect on oxygen affinity of whole blood.