Molecular and cellular characterization of a new a-Thalassemia mutation (HBA2:c.94A>C) generating an alternative splice site and a premature stop codon
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The identification of a-thalassemia (a-thal) due to point mutations has been increasing significantly with the advancement of molecular diagnostic tools. We describe here the molecular and cellular characteristics of the thalassemia mutation HBA2:c.94A>C, a novel point mutation affecting the a2-globin gene, causing a mild a-thal phenotype in a male patient of undisclosed ethnicity, investigated for unexplained microcytosis. The detected mutation is located at the penultimate nucleotide (nt) of the first exon which we postulated might affect pre mRNA splicing. While an in silico analysis did not predict any aberrant splice variants, experimental analysis using our in vitro model for gene expression studies showed utilization of a cryptic splice site at codon 15 that resulted in an aberrant splice variant. As a result, a frameshift in the reading frame of the mature mRNA was produced, leading to the formation of a premature termination codon (PTC) between codons 48 and 49 in exon 2. This in turn leads to nonsense mediated mRNA decay (NMD) and the phenotype of a-thal. Copyright © Informa Healthcare USA, Inc.
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In vitro characterization of the a-thalassemia point mutation HBA2:c.95+1G>A [IVS-I-1(G>A) (a2)]Qadah, T.; Finlayson, J.; Ghassemifar, Reza (2012)The a-thalassemias are a group of disorders occurring as a result of decreased synthesis of a-globin chains, most commonly due to deletions of a-globin genes. Detection of a-thalassemia (a-thal) caused by point mutations ...
Qadah, T.; Finlayson, J.; Newbound, C.; Pell, N.; Jennens, M.; Holmes, P.; Grey, D.; Beilby, J.; Ghassemifar, Reza (2012)Aim: While the phenotype for heterozygous beta-thalassaemia is straightforward, it is more difficult to confirm a causative relationship for mutations in the alpha-globin genes. The aim of this study was to generate an ...
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 codonQadah, T.; Finlayson, J.; Joly, P.; Ghassemifar, Reza (2014)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 ...