Variability in the fetal hemoglobin level of the normal adult.

We analyzed blood samples from more than 200 normal adults, and quantified their Hb F by cation-exchange high-performance liquid chromatography. In several subjects with slightly elevated Hb F (0.4-4.3%), we determined the Ggamma levels in the Hb F and DNA sequence variations in the locus control region II and in the Ggamma and Agamma promoters. About 25% of the approximately 200 normal teenaged high school students had elevated Hb F; detailed analyses of some 20 students, selected at random, identified most as females with a homozygosity for the C-->T variation at position -158 (Ggamma). One 11-year-old boy was heterozygous for the A-->G change at position -161 (Ggamma); he and two of his relatives had approximately 4% Hb F, high Ggamma values, and a high level of (mainly) Ggamma-mRNA. Nearly 40 normal adults from Macedonia and from Georgia (mostly Caucasians) were tentatively identified as Swiss HPFH heterozygotes because slightly elevated Hb F levels were observed at least once. Many of these persons were heterozygous or homozygous for the C-->T mutation at -158 (Ggamma), and a few carried a gamma-globin gene triplication. The C-->T change appears to be an important factor predisposing the adult to increased Hb F production. Evidence suggests a gene dose effect in (mildly) anemic adults; however, other factors besides the C-->T change at -158 (Ggamma), including factors not linked to the beta-globin region, may cause an increase in gamma-chain synthesis.

Co-inheritance of Hb D-Punjab (codon 121; GAA-->CAA) and beta (0) -thalassemia (IVS-II-1;G-->A).

PURPOSE: Homozygosity for Hb D-Punjab (or Hb D-Los Angeles; codon 121; GAA-->CAA) is rare among Arabs. The co-inheritance of Hb D with beta(0)-thalassemia trait is even rarer, with only 10 previous cases reported worldwide. PATIENTS AND METHODS: We present clinical and hematological data for two Hb D homozygotes and three compound heterozygotes for Hb D-Punjab and beta(0)-thalassemia (IVS-II-1; G-->A). All the individuals belong to a consanguineous Kuwaiti Arab family. The hemoglobin variant and the beta-thalassemia allele were characterized by sequencing, allele-specific amplification, and oligonucleotide hybridization. RESULTS: The hematology was unremarkable except for a moderate elevation of Hb F (3-4%) and significant hypochromia and microcytosis in the subject with Hb D/beta(0)-thalassemia. CONCLUSION: This report confirms the benign nature of homozygosity for Hb D.

Hb Bibba or alpha 2 136(H19)Leu-->Pro beta 2 in a Caucasian family from Alabama.

Several members of a large Caucasian family who presented with a congenital Heinz body hemolytic anemia were found to be carriers of the unstable Hb Bibba or alpha 2 136(H19)Leu-->Pro beta 2. Identification by protein analysis was hampered by the instability of the variant which complicated its isolation from shipped blood samples. Moreover, the detection of the CTG-->CCG mutation at codon 136 of the alpha 2 gene required the substitution of dGTP by dITP during the DNA sequencing process to prevent the occurrence of secondary structures and compressions in the sequencing gel. The first Hb Bibba heterozygote, characterized in 1968 (1), is believed to be a member of this family. The clinical expression of the disease is surprisingly variable.

Hb Anamosa or alpha 2(111)(G18)Ala-->Val beta 2 (alpha 2 mutation) and Hb Mulhacen or alpha 2(123)(H6)Ala-->Ser beta 2 (alpha 1 mutation) are two silent, stable variants detected by sequencing of amplified DNA.

We have identified silent amino acid substitutions in two alpha chain variants present in families from Iowa, USA, and Granada, Spain. Both involve an alanine residue in the core peptide, namely Ala-->Val at position 111 (codon change in the alpha 2 gene; GCC->GTC; Hb Anamosa) and Ala-->Ser at position 123 (codon change in the alpha 1 gene; GCC-->TCC; Hb Mulhacen). The two variants are stable. Sequencing of the amplified alpha 2- and alpha 1-globin genes greatly facilitated the characterization of the two variants.

Hb Alesha or alpha 2 beta (2)67(E11)Val-->Met: a new unstable hemoglobin variant identified through sequencing of amplified DNA.

We have identified a valine-->methionine mutation at position 67 of the beta chain in the hemoglobin of a young Russian patient with severe hemolytic disease, anemia, splenomegaly, Heinz body formation, and continued requirement for blood transfusions despite an early splenectomy. Sequencing of amplified DNA readily identified a GTG-->ATG mutation at codon 67. The introduction of the larger methionine residue into the heme pocket, and the loss of the bonds between valine at beta 67 and the heme group, adequately account for the severe instability of Hb Alesha and the serious clinical condition of its carrier.