The modifying effect of Xmn1-HBG2 on thalassemic phenotype is associated with its linked elements in the beta globin locus control region, including the palindromic site at 5'HS4.
The core sequence of 5'HS4-beta globin locus control region and Xmn1-HBG2 site were analyzed and compared among 86 thalassemia patients with homozygous or compound heterozygous beta globin gene mutations and 101 normal individuals. Frequency of the G allele in the polymorphic palindromic sequence of 5'HS4 (TGGGG A/G CCCCA) and positive Xmn1-HBG2 profile was significantly higher in thalassemia patients compared to the normal population. Linkage disequilibrium was observed between the G allele and positive Xmn1-HBG2 profile in patient population. Furthermore, dominance of IVSII-1 in the mutation spectrum of the patients enabled us to identify linkage disequilibrium relationships between IVSII-1, positive Xmn1-HBG2 and the G allele at 5'HS4. The frequency of milder clinical phenotype was significantly higher in patients with GG/++ than cases with AA/-- genotypic pattern in 5'HS4/Xmn1-HBG2 loci. These data together with biochemical evidence suggesting a role for the A/G polymorphism at 5'HS4 palindromic site on modifying chromatin structure and in the absence of any evidence from functional studies relating the Xmn1-HBG2 site to the increased gamma chain expression, suggest that the phenotype modifying role long time assigned to Xmn1-HBG2 is possibly played by more functionally potent elements linked to it in LCR.
Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran. nneisha@gmail.com
Maryam
M
Neishabury
Shahbaz
S
Zamani
Azita
A
Azarkeivan
Seyedeh Sedigheh
SS
Abedini
Hossein
H
Darvish
Fahimeh
F
Zamani
Hossein
H
Najmabadi
D000293:Adolescent; D000328:Adult; D000483:Alleles; D016022:Case-Control Studies; D002648:Child; D002843:Chromatin / Q000235:genetics*; D005260:Female; D005799:Genes, Dominant; D056726:Genetic Association Studies; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D055029:Inverted Repeat Sequences; D007492:Iran; D015810:Linkage Disequilibrium; D019901:Locus Control Region / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D011110:Polymorphism, Genetic; D055544:beta-Globins / Q000737:chemistry / Q000235:genetics*; D017086:beta-Thalassemia / Q000235:genetics*
D002843:Chromatin; D055544:beta-Globins