Molecular characterization of ß-thalassemia intermedia: a report from Iran.

Thalassemia intermedia is a clinical definition applied to patients whose clinical phenotype is milder than thalassemia major. To characterize different common mechanisms involving in pathogenesis of moderate to severe ß-thalassemia intermedia, we have studied four factors in 38 Iranian patients with thalassemia intermedia: ß-globin gene mutation, deletion in α-globin genes, presence of XmnI polymprphism and RFLP haplotype at ß-globin gene cluster. The results showed that 84.4% of patients were associated with severe mutations in ß-globin gene, mainly IVSII-1(G to A) (56.4%). The positive XmnI polymorphism was seen in 76.9% of the studied alleles which showed strong linkage to ß° mutations and high level of fetal hemoglobin. Co-existence of α-globin gene deletions, ß(+) mutation and the most frequent of RFLP haplotype (-/-, +/+, -/+, +/+, +/+, +/+, -/-) were seen in 7.7, 12.8 and 17.9%, respectively. In this group of our study it seems the main ameliorating factor in the patients was co-inheritance of a positive XmnI polymorphism with ß° mutation especially IVSII-1, which were associated with increased production of fetal hemoglobin. However, the other probable genetic factors should be investigated to describe genotype-phenotype correlation in thalassemia intermedia patients.

Association between ABCB1-T1236C polymorphism and drug-resistant epilepsy in Iranian female patients.

BACKGROUND: One third of epileptic patients are resistant to several anti-epileptic drugs (AED). P-glycoprotein (P-gp) is an efflux transporter encoded by ATP-binding cassette subfamily B member 1 (ABCB1) gene that excludes drugs from the cells and plays a significant role in AEDs resistance. Over-expression of P-gp could be a result of polymorphisms in ABCB1 gene. We studied the association of T129C and T1236C single-nucleotide polymorphisms (SNP) of ABCB1 gene with drug-resistant epilepsy in Iranian epileptics. METHODS: DNA samples were obtained from 200 healthy controls and 332 epileptic patients, of whom 200 were drug responsive and 132 drug resistant. The frequencies of the genotypes of the two SNP were determined by polymerase chain reaction followed by restriction fragment length polymorphism. RESULTS: No significant association was found between T129C and T1236C genotypes and drug-resistant epilepsy neither in adults nor in children. However, the risk of drug resistance was higher in female patients with 1236CC (P = 0.02) or CT (P = 0.008) genotype than in those with TT genotype. The risk of drug resistance was also higher in patients with symptomatic epilepsies with 1236CC (P = 0.02) or CT (P = 0.004) genotype than in those with TT genotype. The risk of drug resistance was lower in patients with idiopathic epilepsies with 129TT genotype (P = 0.001) than in those with CT genotype. CONCLUSION: Our results indicate that T1236C polymorphism is associated with drug resistance in Iranian female epileptic patients. Replication studies with large sample sizes are needed to confirm our results.

Molecular analysis of gamma-globin promoters, HS-111 and 3'HS1, in beta-thalassemia intermedia patients associated with high levels of Hb F.

The nucleotide (nt) variations in the promoter region of the gamma-globin genes, HS-111 and 3'HS1 regions, were studied in Iranian patients with beta-thalassemia intermedia (beta-TI), beta-thalassemia major (beta-TM) and healthy individuals. Of the five nt variations at the 5' end of the (A)gamma-globin gene, -369 (C>G), -611 (-T) and -603/604 (GA>AG) were found in all samples, whereas -588 (A>G) and -AAGC at -222 to -225 were found at different frequencies in the studied groups. Therefore, the -369, -611 and -603/604 variations were considered common mutations in this population, and the difference with respect to the -AAGC deletion was not significant. However, the A allele of the -588 variation and [+] allele of the XmnI polymorphism were more frequent in beta-TI patients, especially those who had the IVS-II-1(G>A)/IVS-II-1(G>A) genotype. The + allele of XmnI also had complete correlation with the A allele of -588 variation. The HS-111 (-21 A) variation also showed association with beta-TI patients who had high levels of Hb F. Bearing in mind that the -588 variation lies within the postulated adult-specific silencer region and that the majority of beta-TI patients had allele A, then it can be envisaged that this allele could have a role in altering the repressor function at this region. Therefore, the A allele of -588, [+] allele of XmnI and HS-111 (-21 A) variation are useful genetic markers to differentiate between beta-TM and beta-TI patients. However, these nt changes alone may not be the only elements raising the level of Hb F, other regulatory and modifying factors also play a role in Hb F production.