Molecular and cellular analysis of a novel HBA2 mutation (HBA2: C.94A>G) shows activation of a cryptic splice site and generation of a premature termination codon

T. Qadah, Jill Finlayson, P. Joly, Reza Ghassemifar

    Research output: Contribution to journalArticle

    1 Citation (Scopus)

    Abstract

    In this study, we describe the clinical features and provide experimental analyses of a novel point mutation affecting the penultimate nucleotide of the first exon of the HBA2 (HBA2: c.94A>G) gene identified in a 26-year-old female who also carries a heterozygous Hb E (HBB: c.79G>A) variant. The aim of the study was to investigate the impact of this point mutation on the transcriptional activity of the HBA2 gene using a combination of an initial in silico prediction followed by in vitro mutagenesis and transcriptional activity assessment. The analyses revealed that the HBA2: c.94A>G point mutation causes the activation of a cryptic splice site located 49bp upstream of the exon1-intron1 boundary in both HBA2 long and short isoforms, thus generating a frameshift and a premature termination codon between codons 48 and 49 in the second exon. A rapid degradation of the aberrantly spliced transcripts by the nonsense mediated decay (NMD) surveillance system is highly indicative of an α-thalassemia (α-thal) phenotype. However, the abnormal mRNA may not be entirely degraded since the proband presents a slight splenomegaly that could be the sign of extra vascular hemolysis. © 2014 Informa Healthcare USA, Inc.
    Original languageEnglish
    Pages (from-to)13-18
    JournalHemoglobin
    Volume38
    Issue number1
    DOIs
    Publication statusPublished - 2014

    Fingerprint

    RNA Splice Sites
    Nonsense Codon
    Point Mutation
    Exons
    Genes
    Chemical activation
    Mutagenesis
    Mutation
    Protein Isoforms
    Thalassemia
    Nucleotides
    Splenomegaly
    Hemolysis
    Codon
    Degradation
    Computer Simulation
    Messenger RNA
    Blood Vessels
    Delivery of Health Care
    Phenotype

    Cite this

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    title = "Molecular and cellular analysis of a novel HBA2 mutation (HBA2: C.94A>G) shows activation of a cryptic splice site and generation of a premature termination codon",
    abstract = "In this study, we describe the clinical features and provide experimental analyses of a novel point mutation affecting the penultimate nucleotide of the first exon of the HBA2 (HBA2: c.94A>G) gene identified in a 26-year-old female who also carries a heterozygous Hb E (HBB: c.79G>A) variant. The aim of the study was to investigate the impact of this point mutation on the transcriptional activity of the HBA2 gene using a combination of an initial in silico prediction followed by in vitro mutagenesis and transcriptional activity assessment. The analyses revealed that the HBA2: c.94A>G point mutation causes the activation of a cryptic splice site located 49bp upstream of the exon1-intron1 boundary in both HBA2 long and short isoforms, thus generating a frameshift and a premature termination codon between codons 48 and 49 in the second exon. A rapid degradation of the aberrantly spliced transcripts by the nonsense mediated decay (NMD) surveillance system is highly indicative of an α-thalassemia (α-thal) phenotype. However, the abnormal mRNA may not be entirely degraded since the proband presents a slight splenomegaly that could be the sign of extra vascular hemolysis. {\circledC} 2014 Informa Healthcare USA, Inc.",
    author = "T. Qadah and Jill Finlayson and P. Joly and Reza Ghassemifar",
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    doi = "10.3109/03630269.2013.858639",
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    Molecular and cellular analysis of a novel HBA2 mutation (HBA2: C.94A>G) shows activation of a cryptic splice site and generation of a premature termination codon. / Qadah, T.; Finlayson, Jill; Joly, P.; Ghassemifar, Reza.

    In: Hemoglobin, Vol. 38, No. 1, 2014, p. 13-18.

    Research output: Contribution to journalArticle

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    AB - In this study, we describe the clinical features and provide experimental analyses of a novel point mutation affecting the penultimate nucleotide of the first exon of the HBA2 (HBA2: c.94A>G) gene identified in a 26-year-old female who also carries a heterozygous Hb E (HBB: c.79G>A) variant. The aim of the study was to investigate the impact of this point mutation on the transcriptional activity of the HBA2 gene using a combination of an initial in silico prediction followed by in vitro mutagenesis and transcriptional activity assessment. The analyses revealed that the HBA2: c.94A>G point mutation causes the activation of a cryptic splice site located 49bp upstream of the exon1-intron1 boundary in both HBA2 long and short isoforms, thus generating a frameshift and a premature termination codon between codons 48 and 49 in the second exon. A rapid degradation of the aberrantly spliced transcripts by the nonsense mediated decay (NMD) surveillance system is highly indicative of an α-thalassemia (α-thal) phenotype. However, the abnormal mRNA may not be entirely degraded since the proband presents a slight splenomegaly that could be the sign of extra vascular hemolysis. © 2014 Informa Healthcare USA, Inc.

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