title: Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia.
abstract: BACKGROUND
  Mutations in TERC, the gene for the RNA component of telomerase, cause short telomeres in congenital aplastic anemia and in some cases of apparently acquired hematopoietic failure. We investigated whether mutations in genes for other components of telomerase also occur in aplastic anemia.
  
  
  METHODS
  We screened blood or marrow cells from 124 patients with apparently acquired aplastic anemia and 282 control subjects for sequence variations in the TERT, DKC1, NHP2, and NOP10 genes; an additional 81 patients and 246 controls were examined for genetic variations in TERT. Telomere lengths and the telomerase activity of peripheral-blood leukocytes were evaluated in patients carrying genetic variants. Identified mutations were transfected into telomerase-deficient cell lines to examine their effects and their mechanism of action on telomerase function.
  
  
  RESULTS
  Five heterozygous, nonsynonymous mutations (which cause an amino acid change in the corresponding protein) were identified in TERT, the gene for the telomerase reverse transcriptase catalytic enzyme, among seven unrelated patients. Leukocytes from these patients had short telomeres and low telomerase enzymatic activity. In three of these patients, the mutation was also detected in buccal mucosa cells. Family members carrying the mutations also had short telomeres and reduced telomerase activity but no evident hematologic abnormality. The results of coexpression of wild-type TERT and TERT with aplastic anemia-associated mutations in a telomerase-deficient cell line suggested that haploinsufficiency was the mechanism of telomere shortening due to TERT mutations.
  
  
  CONCLUSIONS
  Heterozygous mutations in the TERT gene impair telomerase activity by haploinsufficiency and may be risk factors for marrow failure.
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md 20892-1202, USA.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Rodrigo T
authors.initials: RT
authors.lastname: Calado
authors.forename: Hinh
authors.initials: H
authors.lastname: Ly
authors.forename: Sachiko
authors.initials: S
authors.lastname: Kajigaya
authors.forename: Gabriela M
authors.initials: GM
authors.lastname: Baerlocher
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.forename: Peter M
authors.initials: PM
authors.lastname: Lansdorp
authors.forename: Neal S
authors.initials: NS
authors.lastname: Young
mesh_terms: D000328:Adult; D000368:Aged; D000741:Anemia, Aplastic / Q000201:enzymology / Q000235:genetics*; D001854:Bone Marrow Cells; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins; D005260:Female; D015870:Gene Expression; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016133:Polymerase Chain Reaction; D012313:RNA; D012307:Risk Factors; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism* / Q000648:ultrastructure; D016615:Telomere / Q000648:ultrastructure
chemical_list: D004268:DNA-Binding Proteins; C422952:telomerase RNA; D012313:RNA; C509186:TERT protein, human; D019098:Telomerase