 Methylation has been shown to functionally impact Sp1 sites as well as a CREB binding site.It has been shown that the CREB site must be intact for normal promoter activity to occur and methylation at the Sp1 sites may affect promoter activity.Proximal "NF1" promoter/5’ UTR methylation has been analyzed in tissues from NF1 patients, with the idea that reduced transcription as a result of methylation could be a “second hit” mechanism equivalent to a somatic mutation.