title: Targeted disruption of Dkc1, the gene mutated in X-linked dyskeratosis congenita, causes embryonic lethality in mice.
abstract: Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome associated with increased cancer susceptibility. The X-linked form is due to mutations in the DKC1 gene encoding dyskerin, a nucleolar protein predicted to be involved in rRNA processing and associated with the telomerase complex. Available evidence suggests the pathology of DC is due to telomerase defects. We have used the inducible Cre/loxP system to produce deletions in the murine Dkc1 gene in early embryogenesis. A large deletion lacking exons 12-15 and a small deletion lacking only the last exon, were produced. We found both deletions showed a parent-of-origin effect with 100% embryonic lethality when the mutation occurred on the maternal Dkc1. Embryonic analysis at day E7.5 and E9.5 showed no male embryos carrying either deletion whereas females with maternally derived deletions died around day E9.5, with degeneration of the extra embryonic tissue, in which the paternal X-chromosome is inactivated. Female mice carrying the deletion in the paternally derived Dkc1 show extreme skewing of X-inactivation with the wild type X-chromosome active in all cells. Since mice with no telomerase are viable in the first generations the lethality we observe is unlikely to be due to the effects of mutated dyskerin on telomerase activity.
authors.affiliation: Department of Internal Medicine, Div Hematology, Washington University School of Medicine, St Louis, Missouri, MO 63110, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: He
authors.forename: Sandra
authors.initials: S
authors.lastname: Navarrete
authors.forename: Murek
authors.initials: M
authors.lastname: Jasinski
authors.forename: Tom
authors.initials: T
authors.lastname: Vulliamy
authors.forename: Inderjeet
authors.initials: I
authors.lastname: Dokal
authors.forename: Monica
authors.initials: M
authors.lastname: Bessler
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Mason
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics*; D004303:Dosage Compensation, Genetic; D019871:Dyskeratosis Congenita / Q000235:genetics*; D005313:Fetal Death / Q000235:genetics*; D005818:Genetic Engineering / Q000379:methods; D019426:Integrases / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D017384:Sequence Deletion; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; C112148:DKC1 protein, human; D009687:Nuclear Proteins; D014764:Viral Proteins; C045073:Cre recombinase; D019426:Integrases; D019098:Telomerase