Identification and functional characterization of novel telomerase variant alleles in Japanese patients with bone-marrow failure syndromes

Junko Takeuchi, Hinh Ly, Hiroki Yamaguchi, Kathryn A. Carroll, Fumiko Kosaka, Kazuhiro Sawaguchi, Yoshio Mitamura, Ayako Watanabe, Seiji Gomi, Koiti Inokuchi, Kazuo Dan

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22 Scopus citations


As the incidence of bone-marrow failure syndromes (BMFS) is 2-3× higher in East Asia than in the West, we examined peripheral blood or marrow cells of 100 Japanese patients for possible pathogenic mutations in the two main components of the telomere-synthesizing enzyme telomerase (hTERC RNA and hTERT protein) that have recently been implicated in the disease pathogenesis. We analyzed samples collected from 34 patients with acquired aplastic anemia (AA), 66 patients with myelodysplastic syndromes (MDS) and 120 healthy controls. In addition to two polymorphic germ-line sequence changes (n-771A/G and n-714 C insertion) in the promoter region of hTERC and eleven hTERT polymorphisms that were identified in both patients and healthy individuals, we found a novel germ-line C323T mutation in the hTERC RNA in an MDS patient only. This heterozygous C323T mutation abolished telomerase enzymatic activity and functioned in a haploinsufficiency manner to modulate telomerase activity in cells. In summary, this study reports a novel telomerase natural variant that abolishes telomerase function, which may lead to telomere shortening and marrow hypocellularity in patients with BMFS. This study also highlights the rarity of genetic alterations in BMFS patients in Japan, which suggests that other factors may play a more prominent role in the disease pathogenesis in East Asia.

Original languageEnglish (US)
Pages (from-to)185-191
Number of pages7
JournalBlood Cells, Molecules, and Diseases
Issue number2
StatePublished - Mar 2008

Bibliographical note

Funding Information:
This work was supported in part by grants from the American Cancer Society (RSG-06-162-01-GMC) and the AA and MDS International Foundation, Inc. to H.L. We wish to thank the patients and their families for their support and participation in the study.

Copyright 2009 Elsevier B.V., All rights reserved.


  • Aplastic anemia
  • Bone-marrow failure syndromes
  • Myelodysplastic syndromes
  • Telomerase
  • Telomeres
  • hTER
  • hTERC
  • hTERT
  • hTR


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