Background: Spinal muscular atrophy (SMA) is a common recessive disorder, characterized by degeneration of motor neurons of the spinal cord. Deletions, conversions, or mutations of the survival motor neuron gene (SMN) are responsible for SMA. A highly homologous centromeric copy of the SMN gene (SMNc) remains intact in SMA patients. However, there is an inverse correlation between the amount of the SMNc gene product and the clinical severity of the disease. An understanding of SMN and SMNc gene regulation is, therefore, an important step towards therapy for SMA.
Results: We identified a candidate Interferon-Stimulated Response Element (ISRE), overlapping with an Interferon Regulatory Factors binding motif (IRF-E) in the promoter region of SMN and SMNc genes. Both ISRE and IRF-E motifs are involved in mediating transcriptional induction of interferon-stimulated gene expression. We, therefore, investigated whether SMN and SMNc genes were regulated by interferons (IFN). Here we show that both IFN-beta and IFN-gamma rapidly induced SMN and SMNc mRNA and protein expression in various cell lines. The transcription factor IRF-1 bound to the candidate ISRE/IRF-E sequence of SMN and SMNc genes in vitro and overexpression of IRF-1 induced expression of both genes in transfection assays. IRF-1 is, therefore, at least in part responsible for the induction of SMN and SMNc by IFNs. In primary culture of fibroblasts from SMA patients, IFN-beta and IFN-gamma induced SMNc gene expression and restored protein defect.