Maria Plonczynski

BETA-THALASSEMIA IN SOUTHWESTERN IRAN

Seventeen unrelated beta-thalassemia patients or carriers from Southwestern Iran were examined for the beta-globin gene mutations by polymerase chain reaction amplification of the beta-globin gene and direct genomic sequencing, or by the method of allele-specific oligonucleotide hybridization. Their clinical and hematological characteristics were also recorded. Of 26 potential thalassemia-causing chromosomes examined, 10 different mutations were found. The IVS-II-1 (G-->A) mutation was the most frequent (31%) followed by the IVS-I-6 (T-->C) mutation (15%). Eight mutations were initially described in Mediterranean populations and two were of Kurdish origin. Four of these mutations, both initially described in the Mediterranean region, are reported here for the first time in Iranians. The unexpectedly high number of different mutations that account for beta-thalassemia in this region of Iran suggest migration of chromosomes from distant places and genetic admixture.

β-Globin gene haplotype in Hb SC disease

We asked the question, is the haplotype found with the sickle hemoglobin gene associated with different hematological characteristics in patients who were combined heterozygotes for sickle hemoglobin and hemoglobin C (Hb SC disease)? In 73 adults with Hb SC disease, a Benin haplotype chromosome was present in 56%, and Bantu (or Central African Republic; CAR), Senegal, and atypical haplotype chromosomes were found in 25%, 6%, and 12%, respectively. No significant differences were found in hematological characteristics or fetal hemoglobin levels of patients with Benin/C, CAR/C, Senegal/C, and atypical/C haplotypes. There were 71%C I, 18% C II, and 11% other βc haplotypes. Fetal hemoglobin levels are lower in Hb SC disease than in sickle‐cell anemia. Perhaps because haplotype has no discernible effect on fetal hemoglobin level in Hb SC disease, it does not modulate its hematological features.

Genetic studies suggest a multicentric origin for Hb G-coushatta [β22(B4)Glu→Ala]

Hb G-Coushatta [beta22(B4)Glu-->Ala] is found in geographically separated ethnic groups. Commonest along the Silk Road region of China but also present in the North American Coushatta, we sought to determine whether this variant had a unicentric or multicentric origin. We examined the haplotype of the beta-globin gene cluster in two Chinese families and in five Louisiana Coushatta heterozygous for this mutation. Chinese and Louisiana Coushatta had different haplotypes associated with the identical Hb G mutation. These haplotypes were defined by the presence of a HindIII restriction site in the Agamma-globin gene and AvaII restriction site in the beta-globin gene in Chinese subjects and their absence in the Louisiana Coushatta. We found a CAC at codon beta2 (beta-globin gene framework 1 or 2) linked to the Hb G-Coushatta gene in Chinese, and a CAT (framework 3) in Louisiana Coushatta, indicating different beta-globin gene frameworks. Both the Hb G-Coushatta mutation (GAA-->GCA) and the codon 2 CAC-->CAT polymorphism are normal delta-globin gene sequences, suggesting the possibility of gene conversion. We conclude that Hb G-Coushatta had at least two independent origins. This could be due to separate mutations at codon beta22 in Chinese and Louisiana Coushatta, a mutation at this codon and a beta-->delta conversion, or two beta-->delta gene conversion events.

β-Thalassemia Intermedia with Exceptionally High Hemoglobin A2: Relationship to Mutations in the β-Gene Promoter

Small deletions of the 5′ portion of the β-globin gene that remove the promoters but stop 3′ to the δ-globin gene are recognized as the sole cause of β-thalassemia with exceptionally high hemoglobin A2 (HbA2) levels. Two patients with β-thalassemia intermedia and exceptionally high levels of HbA2 (10.4 and 12.0%) were examined. One patient was a combined heterozygote for the − 88 C→T and a novel − 87 C→A mutation, while the other was homozygous for the − 29 A→G β+-thalassemia mutation. The remainder of the β genes were normal. There was no evidence for deletions involving the 5′ portion of the β gene or the region between the β and δ genes. Gene mapping studies excluded the possibility of a βδ-anti-Lepore hemoglobin gene with β promoters and δ coding sequences. There were no mutations in the promoters of the Gγ or Aγ- globin genes that have been associated with the hereditary persistence of HbF phenotype. The δ-globin gene promoters were normal from codon 17 to position − 145 relative to the mRNA capping site. There appears to be considerable heterogeneity of HbA2 and HbF levels in patients who are homozygous or mixed heterozygotes for mutations in the TATA box and other promoter elements of the β-globin gene. The capacity for proteolysis within the erythrocyte may vary among individuals. The authors hypothesize that in the exceptionally high HbA2 β-thalassemia intermedia phenotype, proteolysis of superfluous α-globin chains is less efficient than in patients with customary levels of HbA2. The relative surfeit of α-chains may combine with δ-globin and account for the unusually high HbA2 levels.

Double Heterozygosity for the Codon β 39 C-to-T Nonsense Mutation and a Triplicate α-Globin Gene Locus Can Cause "Dominantly" Inherited β-Thalassemia Intermedia

ABSTRACT Background A β -thalassemia intermedia phenotype can be caused by multiple genotypes. Methods We studied a family where the mother was hematologically normal and both father and daughter had β -thalassemia intermedia. Results Both affected individuals were heterozygous for a codon 39 C AG-to- T AG mutation. They also were heterozygous for a triplicate α -globin gene locus ( ααα anti 3.7 ). Conclusions This compound heterozygous condition of a β 39 C-to-T mutation and triplicate α-globin gene increases α : β -globin chain imbalance and accounts for the presence of β-thalassemia intermedia. The proband received both an abnormal β-globin gene and a triplicate α -globin locus from her father. Although the phenotype seems to be dominantly inherited, because of independent segregation of the α - and β -globin genes, it is more accurately an example of polygenic inheritance.