Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia

Hiroki Yamaguchi, Rodrigo T. Calado, Hinh Ly, Sachiko Kajigaya, Gabriela M. Baerlocher, Stephen J. Chanock, Peter M. Lansdorp, Neal S. Young

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1413-1424
Number of pages12
JournalNew England Journal of Medicine
Volume352
Issue number14
DOIs
StatePublished - Apr 7 2005
Externally publishedYes

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Aplastic Anemia
Telomerase
Mutation
Genes
Telomere
Gene Components
Haploinsufficiency
Leukocytes
Bone Marrow
Telomere Shortening
Cell Line
Mouth Mucosa
Amino Acids

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Yamaguchi, H., Calado, R. T., Ly, H., Kajigaya, S., Baerlocher, G. M., Chanock, S. J., ... Young, N. S. (2005). Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. New England Journal of Medicine, 352(14), 1413-1424. https://doi.org/10.1056/NEJMoa042980

Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. / Yamaguchi, Hiroki; Calado, Rodrigo T.; Ly, Hinh; Kajigaya, Sachiko; Baerlocher, Gabriela M.; Chanock, Stephen J.; Lansdorp, Peter M.; Young, Neal S.

In: New England Journal of Medicine, Vol. 352, No. 14, 07.04.2005, p. 1413-1424.

Research output: Contribution to journalArticle

Yamaguchi, H, Calado, RT, Ly, H, Kajigaya, S, Baerlocher, GM, Chanock, SJ, Lansdorp, PM & Young, NS 2005, 'Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia', New England Journal of Medicine, vol. 352, no. 14, pp. 1413-1424. https://doi.org/10.1056/NEJMoa042980
Yamaguchi H, Calado RT, Ly H, Kajigaya S, Baerlocher GM, Chanock SJ et al. Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. New England Journal of Medicine. 2005 Apr 7;352(14):1413-1424. https://doi.org/10.1056/NEJMoa042980
Yamaguchi, Hiroki ; Calado, Rodrigo T. ; Ly, Hinh ; Kajigaya, Sachiko ; Baerlocher, Gabriela M. ; Chanock, Stephen J. ; Lansdorp, Peter M. ; Young, Neal S. / Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. In: New England Journal of Medicine. 2005 ; Vol. 352, No. 14. pp. 1413-1424.
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AU - Yamaguchi, Hiroki

AU - Calado, Rodrigo T.

AU - Ly, Hinh

AU - Kajigaya, Sachiko

AU - Baerlocher, Gabriela M.

AU - Chanock, Stephen J.

AU - Lansdorp, Peter M.

AU - Young, Neal S.

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N2 - 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.

AB - 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.

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