Document Detail

Identification and functional characterization of novel telomerase variant alleles in Japanese patients with bone-marrow failure syndromes.
MedLine Citation:
PMID:  17936651     Owner:  NLM     Status:  MEDLINE    
As the incidence of bone-marrow failure syndromes (BMFS) is 2-3x 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.
Junko Takeuchi; Hinh Ly; Hiroki Yamaguchi; Kathryn A Carroll; Fumiko Kosaka; Kazuhiro Sawaguchi; Yoshio Mitamura; Ayako Watanabe; Seiji Gomi; Koiti Inokuchi; Kazuo Dan
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2007-10-23
Journal Detail:
Title:  Blood cells, molecules & diseases     Volume:  40     ISSN:  1079-9796     ISO Abbreviation:  Blood Cells Mol. Dis.     Publication Date:    2008 Mar-Apr
Date Detail:
Created Date:  2008-02-18     Completed Date:  2008-05-06     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  9509932     Medline TA:  Blood Cells Mol Dis     Country:  United States    
Other Details:
Languages:  eng     Pagination:  185-91     Citation Subset:  IM    
Division of Hematology, Department of Internal Medicine, Nippon Medical School, Bunkyo-ku, Tokyo, Japan.
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MeSH Terms
Aged, 80 and over
Bone Marrow / enzymology,  metabolism
Bone Marrow Diseases / epidemiology,  genetics*
Japan / epidemiology
Middle Aged
Molecular Epidemiology
Polymorphism, Genetic
RNA / genetics*
Telomerase / genetics*
Telomere / metabolism
Reg. No./Substance:
0/telomerase RNA; 63231-63-0/RNA; EC

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