X-LINKED DYSKERATOSIS-CONGENITA IS CAUSED BY MUTATIONS IN A HIGHLY CONSERVED GENE WITH PUTATIVE NUCLEOLAR FUNCTIONS

X-linked recessive dyskeratosis congenita (DKC) is a rare bone-marrow failure disorder linked to Xq28. Hybridization screening with 28 candi date cDNAs resulted in the detection of a 3' deletion in one DKC patie nt with a cDNA probe (derived from XAP101). Five different missense mu tations in five unrelated patients were subsequently identified in XAP 101, indicating that it is the gene responsible for X-linked DKC (DKC1 ). DKC1 is highly conserved across species barriers and is the ortholo gue of rat NAP57 and Saccharomyces cerevisiae CBF5. The peptide dysker in contains two TruB pseudouridine (psi) synthase motifs, multiple pho sphorylation sites, and a carboxy-terminal lysine-rich repeat domain. By analogy to the function of the known dyskerin orthologues, involvem ent in the cell cycle and nucleolar function is predicted for the prot ein.