Basal transcription activity of the dyskeratosis congenita gene is mediated by Sp1 and Sp3 and a patient mutation in a Sp1 binding site is associated with decreased promoter activity.

The multisystem disorder dyskeratosis congenita (DKC) is caused by mutations in the DKC1 gene. The protein dyskerin is a component of the box H+ACA small nucleolar RNAs (snoRNAs) and is also functionally associated with the RNA component of the human telomerase. The majority of mutations are missense mutations, although single examples of non-coding mutations have been described. One of these is a point mutation in a putative Sp1 binding site in the 5'-upstream region of the DKC1 gene which presumably represents the promoter region of the gene. In this report, we compare the promoter sequences of both the human and mouse genes and provide a first functional characterisation of the human DKC1 promoter. This includes a characterisation of the disease-associated implications caused by the mutation identified in one patient. By reporter gene analysis, functional regions of the DKC1 promoter were delineated. The core promoter region critical for basal level of transcription was found to lie at -10 to -180. Bandshift- and supershift experiments clearly demonstrated a mutual binding of transcription factors Sp1 and Sp3 to two of five putative GC-box/Sp1-binding sites located within the core promoter region. An additional GC-box interacts only with the Sp1 transcription factor. Further, we provide evidence that the DKC1 mutation in one of the Sp1 binding sites results in reduced promoter activity.