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Previous Volume 352:1413-1424 April 7, 2005 Number 14 Next

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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.

Source Information

From the Hematology Branch, National Heart, Lung, and Blood Institute (H.Y., R.T.C., S.K., N.S.Y.), and the Pediatric Oncology Branch, National Cancer Institute (S.J.C.), National Institutes of Health, Bethesda, Md.; the Experimental Pathology Division, Department of Pathology and Laboratory Medicine, Emory University, Atlanta (H.L.); and the Terry Fox Laboratory, BC Cancer Research Centre (G.M.B., P.M.L.), and the Department of Medicine, University of British Columbia (P.M.L.) — both in Vancouver, B.C., Canada.

Drs. Yamaguchi, Calado, and Ly contributed equally to this article.

Address reprint requests to Dr. Young at the Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, 10 Center Dr., Bldg. 10/CRC, Rm. 3E-5140, Bethesda, MD 20892-1202, or at youngns{at}mail.nih.gov.

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