Functional analysis of a promoter variant of the gene encoding the interferon-gamma receptor chain I.

We analyzed a single nucleotide polymorphism (SNP) at position -56 (T-->C) in the promoter region of the gene encoding the human interferon-gamma receptor ligand-binding chain I (IFN-gammaR1). The mutation was present at similar frequencies in Gabonese children with either mild or severe malaria. Functional investigations of the promoter in a transfected human B-cell line showed lower levels of luciferase reporter gene expression in the presence of the mutation, indicating the importance of this position for promoter activity, and suggesting that this SNP might negatively influence the expression level of IFN-gammaR1 at the cell surface. Further examinations of the DNA sequence at this polymorphic site showed a perfectly matched binding site for the transcription factor activator protein 4 (AP-4) on both strands. Binding sites for other important transcription factors involved in gene expression and regulation of the immune response against infections, including Ikaros 2 (Ik-2), nuclear factor kappaB (NFkappaB), and CETS1p54, are also situated in this region.