X-linked dyskeratosis congenita is predominantly caused by missense mutations in the DKC1 gene

Dyskeratosis congenita is a rare inherited bone marrow-failure syndrome cha racterized by abnormal skin pigmentation, nail dystrophy, and mucosal leuko plakia. More than 80% of patients develop bone-marrow failure, and this is the major cause of premature death. The X-linked form of the disease (MIM 3 05000) has been shown to be caused by mutations in the DKC1 gene. The gene encodes a 514-amino-acid protein, dyskerin, that is homologous to Saccharom yces cerevisiae Cbf5p and rat Nap57 proteins. By analogy to the homologues in other species, dyskerin is predicted to be a nucleolar protein with a ro le in both the biogenesis of ribosomes and, in particular, the pseudouridyl ation of rRNA precursors. We have determined the genomic structure of the D KC1 gene; it consists of 15 exons spanning a region of 15 kb. This has enab led us to screen for mutations in the genomic DNA, by using SSCP analysis. Mutations were detected in 21 of 37 additional families with dyskeratosis c ongenita that were analyzed. These mutations consisted of 11 different sing le-nucleotide substitutions, which resulted in 10 missense mutations and 1 putative splicing mutation within an intron. The missense change A353V was observed in 10 different families and was shown to be a recurring de novo e vent. Two polymorphisms were also detected, one of which resulted in the in sertion of an additional lysine in the carboxy-terminal polylysine domain. It is apparent that X-linked dyskeratosis congenita is predominantly caused by missense mutations; the precise effect on the function of dyskerin rema ins to be determined.