The HbS gene had a limited number of origins during history, and these can be defined by the haplotype (a set of DNA polymorphisms inherited together) of the associated β-globin gene. Five major haplotypes have been identified, and associated with different ethnic groups. These are the Arab Indian haplotype, the Benin haplotype, the Cameroonian haplotype, the Central African Republic (CAR) or Bantu haplotype, and the Senegal haplotype. The polymorphisms defining these haplotypes are associated with fetal hemoglobin, the major modifier of sickle cell disease phenotype and severity. The Arab Indian haplotype, in particular, is associated with unusually high HbF levels (20%), and a significantly less severe clinical presentation. We found a novel (C>T) SNP -68 bp 5' to HBD in this region, expressed in patients with the Arab Indian haplotype, but not sickle cell disease patients expressing other β-globin cluster haplotypes. There is evidence that this -68 (C>T) polymorphism may play a functional role in the hemoglobin expression of these patients, and its effect on globin levels and disease severity is the long-term interest of this study. A previous reporter assay in K562 cells determined that the -68 SNP was associated with decreased δ-globin gene expression. This study aims to clone the HBD region of a patient positive for this SNP into a lentiviral firefly luciferase reporter vector, for use in more physiologically accurate CD34+ erythropoietic progenitor cells. If the mutations in these β-globin gene haplotypes, such as the HBD mutation described in this study, are responsible for the protective effects seen in patients, perhaps some of these genetic locations can serve as targets for therapeutics in sickle cell disease or other blood disorders.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/16291 |
| Date | 08 April 2016 |
| Creators | Gesiotto, Quinto |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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