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 tissue s that are rapidly dividing in the adult, particularly the skin and haemopo ietic system. The X-linked form of the disease is caused by mutations in th e 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-spe cific pseudouridination of rRNA and in humans is also a component of the te lomerase complex. In order to further characterise the disease at the molec ular level, male DC patients from 25 families were screened for mutations i n the DKC1 gene. Sequence variations were detected in 10 of these families. In five families, previously identified mutations were detected. Of the fi ve novel sequence changes, three were coding changes: R158 W, S280R and P38 4L. A fourth sequence change was detected in the 5'-flanking region that di srupts 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 t he importance of screening for mutations that cause the partial aberrant sp licing of mRNA. This is the first report of DKC1 mutations that are predict ed to affect the level of expression of dyskerin. This suggests that a decr ease in the amount of the normal protein may cause the disease.