A telomerase component is defective in the human disease dyskeratosis congenita

Nature. 1999 Dec 2;402(6761):551-5. doi: 10.1038/990141.


The X-linked form of the human disease dyskeratosis congenita (DKC) is caused by mutations in the gene encoding dyskerin. Sufferers have defects in highly regenerative tissues such as skin and bone marrow, chromosome instability and a predisposition to develop certain types of malignancy. Dyskerin is a putative pseudouridine synthase, and it has been suggested that DKC may be caused by a defect in ribosomal RNA processing. Here we show that dyskerin is associated not only with H/ACA small nucleolar RNAs, but also with human telomerase RNA, which contains an H/ACA RNA motif. Telomerase adds simple sequence repeats to chromosome ends using an internal region of its RNA as a template, and is required for the indefinite proliferation of primary human cells. We find that primary fibroblasts and lymphoblasts from DKC-affected males are not detectably deficient in conventional H/ACA small nucleolar RNA accumulation or function; however, DKC cells have a lower level of telomerase RNA, produce lower levels of telomerase activity and have shorter telomeres than matched normal cells. The pathology of DKC is consistent with compromised telomerase function leading to a defect in telomere maintenance, which may limit the proliferative capacity of human somatic cells in epithelia and blood.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Amino Acid Sequence
  • Catalytic Domain
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Nucleolus / genetics
  • Cell Nucleolus / metabolism
  • Cells, Cultured
  • Child
  • DNA-Binding Proteins
  • Dyskeratosis Congenita / enzymology*
  • Dyskeratosis Congenita / genetics
  • Female
  • Humans
  • Male
  • Molecular Sequence Data
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Protein Binding
  • Pseudouridine / metabolism
  • RNA / metabolism
  • RNA Processing, Post-Transcriptional
  • RNA, Ribosomal / genetics
  • RNA, Ribosomal / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Ribonucleoproteins, Small Nucleolar / genetics
  • Ribonucleoproteins, Small Nucleolar / metabolism
  • Telomerase / genetics
  • Telomerase / metabolism*
  • Transfection


  • Cell Cycle Proteins
  • DKC1 protein, human
  • DNA-Binding Proteins
  • Nuclear Proteins
  • RNA, Ribosomal
  • Recombinant Fusion Proteins
  • Ribonucleoproteins, Small Nucleolar
  • telomerase RNA
  • Pseudouridine
  • RNA
  • Telomerase