title: Decreased dyskerin levels as a mechanism of telomere shortening in X-linked dyskeratosis congenita.
abstract: Dyskeratosis congenita (DC) is a premature ageing syndrome characterised by short telomeres. An X-linked form of DC is caused by mutations in DKC1 which encodes dyskerin, a telomerase component that is essential for telomerase RNA stability. However, mutations in DKC1 are identifiable in only half of X-linked DC families. A four generation family with pulmonary fibrosis and features of DC was identified. Affected males showed the classic mucocutaneous features of DC and died prematurely from pulmonary fibrosis. Although there were no coding sequence or splicing variants, genome wide linkage analysis of 16 individuals across four generations identified significant linkage at the DKC1 locus, and was accompanied by reduced dyskerin protein levels in affected males. Decreased dyskerin levels were associated with compromised telomerase RNA levels and very short telomeres. These data identify decreased dyskerin levels as a novel mechanism of DC, and indicate that intact dyskerin levels, in the absence of coding mutations, are critical for telomerase RNA stability and for in vivo telomere maintenance.
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St., CRB 186, Baltimore, MD 21287, USA.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Parry
authors.forename: Jonathan K
authors.initials: JK
authors.lastname: Alder
authors.forename: Stella S
authors.initials: SS
authors.lastname: Lee
authors.forename: John A
authors.initials: JA
authors.lastname: Phillips
authors.forename: James E
authors.initials: JE
authors.lastname: Loyd
authors.forename: Priya
authors.initials: P
authors.lastname: Duggal
authors.forename: Mary
authors.initials: M
authors.lastname: Armanios
mesh_terms: D000293:Adolescent; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002648:Child; D019871:Dyskeratosis Congenita / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008040:Genetic Linkage / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010375:Pedigree; D010641:Phenotype; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012313:RNA / Q000235:genetics / Q000378:metabolism; D050436:Regulatory Elements, Transcriptional / Q000235:genetics; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D016615:Telomere / Q000235:genetics* / Q000378:metabolism*; D049951:X Chromosome Inactivation / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; C112148:DKC1 protein, human; D009687:Nuclear Proteins; C422952:telomerase RNA; D012313:RNA; D019098:Telomerase