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    Molecular characterization of Hb hamilton hill (HBA2: c.388delC), a novel HBA2 variant generating a premature termination codon and truncated HBA2 chain

    Access Status
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    Authors
    Qadah, T.
    Finlayson, J.
    North, E.
    Ghassemifar, Reza
    Date
    2015
    Type
    Journal Article
    
    Metadata
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    Citation
    Qadah, T. and Finlayson, J. and North, E. and Ghassemifar, R. 2015. Molecular characterization of Hb hamilton hill (HBA2: c.388delC), a novel HBA2 variant generating a premature termination codon and truncated HBA2 chain. Hemoglobin. 39 (2): pp. 88-94.
    Source Title
    Hemoglobin
    DOI
    10.3109/03630269.2015.1016958
    ISSN
    0363-0269
    School
    School of Biomedical Sciences
    URI
    http://hdl.handle.net/20.500.11937/6946
    Collection
    • Curtin Research Publications
    Abstract

    In recent years, the identification of a-thalassemias caused by nondeletional mutations has increased significantly due to the advancement of sensitive molecular genetics tools. We report clinical and experimental data for a novel frameshift mutation caused by a single base deletion at position 388 in exon 3 of the a2-globin gene (HBA2: c.388delC; Hb Hamilton Hill), resulting in the phenotype of a-thalassemia (a-thal). Hb Hamilton Hill was identified in an adult female of unknown ethnicity investigated for unexplained microcytosis. Direct DNA sequencing of the HBA2 gene revealed a heterozygous mutation, HBA2: c.388delC, and the molecular effect of this mutation was assessed experimentally using our previously described in vitro model. The experimental analysis involved transfection of a human bladder carcinoma (5637) cell line with expression vectors carrying either HBA2-wild type (HBA2-WT) or HBA2: c.388delC followed by total RNA purification and cDNA synthesis. Both wild type and mutant gene expression was studied and compared at the transcriptional and translational levels using quantitative real time polymerase chain reaction (qReTi-PCR) and immunofluorochemistry (IFC), respectively. Our experimental data showed a significant reduction by 25.0% (p=0.04) in the transcriptional activity generated from HBA2: c.388delC compared to HBA2-WT. As a result of this base deletion, a frameshift in the open reading frame generates a premature termination codon (PTC) at codon 132 of exon 3 resulting in the formation of a truncated a-globin chain. The truncated a-globin chain, observed by the IFC technique, is most likely unstable and undergoes a rapid turnover resulting in the thalassemic phenotype.

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