Disruption of telomerase trafficking by TCAB1 mutation causes dyskeratosis congenita

  1. Steven E. Artandi1,2,8
  1. 1Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA;
  2. 2Cancer Biology Program, Stanford University School of Medicine, Stanford, California 94305, USA;
  3. 3Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland 20892, USA;
  4. 4Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA;
  5. 5Core Genotyping Facility, SAIC-Frederick, Inc., National Cancer Institute at Frederick (NCI-Frederick), National Institutes of Health, Bethesda, Maryland 20892, USA;
  6. 6Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
    1. 7 These authors contributed equally to this work.

    Abstract

    Dyskeratosis congenita (DC) is a genetic disorder of defective tissue maintenance and cancer predisposition caused by short telomeres and impaired stem cell function. Telomerase mutations are thought to precipitate DC by reducing either the catalytic activity or the overall levels of the telomerase complex. However, the underlying genetic mutations and the mechanisms of telomere shortening remain unknown for as many as 50% of DC patients, who lack mutations in genes controlling telomere homeostasis. Here, we show that disruption of telomerase trafficking accounts for unknown cases of DC. We identify DC patients with missense mutations in TCAB1, a telomerase holoenzyme protein that facilitates trafficking of telomerase to Cajal bodies. Compound heterozygous mutations in TCAB1 disrupt telomerase localization to Cajal bodies, resulting in misdirection of telomerase RNA to nucleoli, which prevents telomerase from elongating telomeres. Our findings establish telomerase mislocalization as a novel cause of DC, and suggest that telomerase trafficking defects may contribute more broadly to the pathogenesis of telomere-related disease.

    Keywords

    Footnotes

    • Received October 25, 2010.
    • Accepted November 22, 2010.
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