Identification of novel DKC1 mutations in patients with dyskeratosis congenita: implications for pathophysiology and diagnosis.

Dyskeratosis congenita (DC) is characterised by the failure of those tissues that are rapidly dividing in the adult, particularly the skin and haemopoietic system. The X-linked form of the disease is caused by mutations in the DKC1 gene. To date the only DKC1 mutations detected result in alterations in the amino acid sequence of dyskerin. Dyskerin is the catalytic subunit of the H+ACA box small nucleolar RNA particles responsible for the site-specific pseudouridination of rRNA and in humans is also a component of the telomerase complex. In order to further characterise the disease at the molecular level, male DC patients from 25 families were screened for mutations in the DKC1 gene. Sequence variations were detected in 10 of these families. In five families, previously identified mutations were detected. Of the five novel sequence changes, three were coding changes: R158 W, S280R and P384L. A fourth sequence change was detected in the 5'-flanking region that disrupts a putative Spl transcription factor binding site. An intronic change was also detected that resulted in the partial incorporation of a portion of intron 1 into the mRNA. The identification of this mutation highlights the importance of screening for mutations that cause the partial aberrant splicing of mRNA. This is the first report of DKC1 mutations that are predicted to affect the level of expression of dyskerin. This suggests that a decrease in the amount of the normal protein may cause the disease.