title: Identification and functional characterization of novel telomerase variant alleles in Japanese patients with bone-marrow failure syndromes.
abstract: 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.
authors.affiliation: Division of Hematology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.
authors.forename: Takeuchi
authors.initials: T
authors.lastname: Junko
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Hinh
authors.initials: H
authors.lastname: Ly
authors.affiliation: Division of Hematology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yamaguchi
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Carroll
authors.affiliation: Division of Hematology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.
authors.forename: Kosaka
authors.initials: K
authors.lastname: Fumiko
authors.affiliation: Division of Hematology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.
authors.forename: Sawaguchi
authors.initials: S
authors.lastname: Kazuhiro
authors.affiliation: Division of Hematology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.
authors.forename: Mitamura
authors.initials: M
authors.lastname: Yoshio
authors.affiliation: Division of Hematology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.
authors.forename: Watanabe
authors.initials: W
authors.lastname: Ayako
authors.affiliation: Department of Hematology, Yokohama Minami Kyosai Hospital, Kanagawa, Japan.
authors.forename: Gomi
authors.initials: G
authors.lastname: Seiji
authors.affiliation: Division of Hematology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.
authors.forename: Inokuchi
authors.initials: I
authors.lastname: Koiti
authors.affiliation: Division of Hematology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Dan
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001853:Bone Marrow / Q000201:enzymology / Q000378:metabolism; D001855:Bone Marrow Diseases / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D006801:Humans; D007564:Japan / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D017720:Molecular Epidemiology; D009154:Mutation; D011110:Polymorphism, Genetic; D012313:RNA / Q000235:genetics*; D013577:Syndrome; D019098:Telomerase / Q000235:genetics*; D016615:Telomere / Q000378:metabolism
chemical_list: C422952:telomerase RNA; D012313:RNA; D019098:Telomerase