A?-haplotypes: A new group of genetic markers for thalassemic mutations inside the 5? regulatory region of the human A?-globin gene

Abstract

This study illustrates the relationship between a group of nucleotide variations within the 5' regulatory region of the Agamma-globin gene [Agamma-588 A-->G, Agamma-499 T-->A and the 4-bp deletion (Agamma-225 to -222 AGCA)] and the spectrum of delta- and beta-thalassemia mutations in the Hellenic population. These sequence variations, screened by means of denaturing gradient gel electrophoresis, form four separate frameworks (Agamma-haplotypes), each one of which was found to be linked in cis with certain delta- and beta-thalassemia mutations found in the Hellenic population. In addition, two novel base substitutions inside the 5' regulatory region of the Agamma-globin gene (Agamma-521 C-->A and Ay-500 C-->T) were identified during this study, which together with Agamma-haplotypes seem to be silent polymorphisms during adult life, as indicated by transient expression assays. Our data show that Agamma-haplotypes represent genetic markers for the spectrum of thalassemic mutations, found in the Hellenic population and can constitute an important genetic repository upon which mutations leading to thalassemia and hemoglobinopathies occurred.

Promoter region sequence differences in the A and G gamma globin genes of Brazilian sickle cell anemia patients

“…The molecular data regarding diseases comprise the target gene and a large number of known and unknown DNA changes. These alterations concomitantly modify the expression of several genes, including the gamma globin genes (HBG2 and HBG1), responsible for the synthesis of the γ chains present in fetal hemoglobin (HbF) (2)(3)(4). Gene expression is modulated by a large number of polymorphisms located in the β-globin gene cluster.…”

Mutation screening in the human ɛ-globin gene using single-strand conformation polymorphism analysis

“…1B, C). Apart from the abovementioned SNP in the expected frequencies for the Hellenic population [10], our mutation screening approach of 120 normal chromosomes from adult individuals yielded no other nucleotide change in all samples in the region analyzed. DNA sequencing of 10 randomly selected cases in all 5 fragments confirmed the presence only of the wild-type sequence.…”

Molecular evidences of single mutational events followed by recurrent crossing-overs in the common δ-globin alleles in the Mediterranean area

“…The Hb A2-Yialousa allele has been reported to be associated with the pattern "G, A and −AGCA" of the SNPs upstream the A γ-globin gene (−588 ANG, − 499 TNA, − 222/5 −AGCA) in 25/25 chromosomes in Cyprus (Patrinos et al, 2001). We analyzed 5 unrelated Hb A2-Yialousa homozygotes with DNA sequencing; the first two positions were confirmed, but not the AGCA deletion.…”

“…In spite of this large variability, one mutation, the Hb A2-Yialousa, has 60-80% of relative frequency while the other mutations have been detected in few families (Guiso et al, 1996;De Angioletti et al, 2002;Giambona et al, 2006;Pavlou et al, 2006). Studies of the RFLP-haplotypes (Moi et al, 1988;Trifillis et al, 1993;De Angioletti et al, 2002) or SNPs (Patrinos et al, 2001), carried out in a few families, have led to conflicting hypotheses about the origin of mutant alleles.…”