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Original article
Decreased dyskerin levels as a mechanism of telomere shortening in X-linked dyskeratosis congenita
  1. Erin M Parry1,2,
  2. Jonathan K Alder1,
  3. Stella S Lee3,
  4. John A Phillips III4,
  5. James E Loyd5,
  6. Priya Duggal6,
  7. Mary Armanios1,7
  1. 1Department of Oncology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine Baltimore, Maryland, USA
  2. 2Medical Scientist Training Progra, Johns Hopkins University School of Medicine Baltimore, Maryland, USA
  3. 3Pre-doctoral Training Program in Human Genetics, Johns Hopkins University School of Medicine Baltimore, Maryland, USA
  4. 4Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
  5. 5Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
  6. 6Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA
  7. 7McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine Baltimore, Maryland, USA
  1. Correspondence to Dr Mary Armanios, Department of Oncology, Johns Hopkins University School of Medicine, 1650 Orleans St., CRB 186, Baltimore, MD 21287, USA; marmani1{at}jhmi.edu

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.

  • Telomerase
  • dyskerin
  • dyskeratosis congenita
  • pulmonary fibrosis
  • genetics
  • haematology (incl blood transfusion)
  • respiratory medicine

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Footnotes

  • Funding Other Funders: NIH; Doris Duke Foundation.

  • Patient consent Obtained.

  • Ethics approval Approval was provided from both the Johns Hopkins and Vanderbilt University School of Medicine's Institutional Review Boards.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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