|
|
Blood, 15 December 2004, Vol. 104, No. 13, pp. 3936-3942.
Prepublished online as a Blood First Edition Paper on August 19, 2004; DOI 10.1182/blood-2004-05-1829.
 Previous Article | Table of Contents | Next Article 
HEMATOPOIESIS
Heterozygous telomerase RNA mutations found in dyskeratosis congenita and aplastic anemia reduce telomerase activity via haploinsufficiency
Anna Marrone,
David Stevens,
Tom Vulliamy,
Inderjeet Dokal, and
Philip J. Mason
From the Department of Haematology, Division of Investigative Science, Imperial College London, Hammersmith Hospital, London, United Kingdom.
Mutations in TERC, encoding the RNA component of telomerase, have been found in autosomal dominant dyskeratosis congenita (DC) and aplastic anemia (AA). Several polymorphisms also exist in the TERC gene, making functional testing of potential pathogenic mutations essential. Here, we have tested normal and mutant TERC molecules in 2 telomerase reconstitution assays, 1 in vitro and 1 in transfected telomerase-negative cells. We find that 2 polymorphic mutations G58A and G228A have no effect on telomerase activity in these assays, whereas 6 mutations found in DC and AA cause reduction or abolition of telomerase activity. Mutations in the pseudoknot region of the TERC molecule, C72G, 96-7 CT, GC107-8AG and 110-3GACT reduce the catalytic activity of reconstituted telomerase, whereas mutations in the 3' portion of the molecule C408G and a deletion of the 3' 74 bases have normal activity in vitro but reduced intracellular activity. By analyzing second site mutations that recreate regions of secondary structure but retain the pathogenic mutations we show that mutations C72G, GC107-8AG, and C408G act by disrupting the secondary structure or folding of TERC. Finally, experiments reconstituting telomerase with both normal and mutant TERC molecules suggest the mutations act via haploinsufficiency rather than by a dominant-negative mechanism. (Blood. 2004;104:3936-3942)
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
C. Trahan and F. Dragon
Dyskeratosis congenita mutations in the H/ACA domain of human telomerase RNA affect its assembly into a pre-RNP
RNA,
February 1, 2009;
15(2):
235 - 243.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. He, Y. Wang, X. Guo, S. Ramchandani, J. Ma, M.-F. Shen, D. A. Garcia, Y. Deng, A. S. Multani, M. J. You, et al.
Pot1b Deletion and Telomerase Haploinsufficiency in Mice Initiate an ATR-Dependent DNA Damage Response and Elicit Phenotypes Resembling Dyskeratosis Congenita
Mol. Cell. Biol.,
January 1, 2009;
29(1):
229 - 240.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Lee, R. Reddy, L. Barsky, J. Scholes, H. Chen, W. Shi, and B. Driscoll
Lung alveolar integrity is compromised by telomere shortening in telomerase-null mice
Am J Physiol Lung Cell Mol Physiol,
January 1, 2009;
296(1):
L57 - L70.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. M. Errington, D. Fu, J. M. Y. Wong, and K. Collins
Disease-Associated Human Telomerase RNA Variants Show Loss of Function for Telomere Synthesis without Dominant-Negative Interference
Mol. Cell. Biol.,
October 15, 2008;
28(20):
6510 - 6520.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Hockemeyer, W. Palm, R. C. Wang, S. S. Couto, and T. de Lange
Engineered telomere degradation models dyskeratosis congenita
Genes & Dev.,
July 1, 2008;
22(13):
1773 - 1785.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. D. Mozdy, E. R. Podell, and T. R. Cech
Multiple Yeast Genes, Including Paf1 Complex Genes, Affect Telomere Length via Telomerase RNA Abundance
Mol. Cell. Biol.,
June 15, 2008;
28(12):
4152 - 4161.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Vulliamy, R. Beswick, M. Kirwan, A. Marrone, M. Digweed, A. Walne, and I. Dokal
From the Cover: Mutations in the telomerase component NHP2 cause the premature ageing syndrome dyskeratosis congenita
PNAS,
June 10, 2008;
105(23):
8073 - 8078.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Cao, L. I. Huschtscha, A. S. Nouwens, H. A. Pickett, A. A. Neumann, A. C-M. Chang, C. D. Toouli, T. M. Bryan, and R. R. Reddel
Amplification of Telomerase Reverse Transcriptase Gene in Human Mammary Epithelial Cells with Limiting Telomerase RNA Expression Levels
Cancer Res.,
May 1, 2008;
68(9):
3115 - 3123.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H.-Y. Du, E. Pumbo, P. Manley, J. J. Field, S. J. Bayliss, D. B. Wilson, P. J. Mason, and M. Bessler
Complex inheritance pattern of dyskeratosis congenita in two families with 2 different mutations in the telomerase reverse transcriptase gene
Blood,
February 1, 2008;
111(3):
1128 - 1130.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Marrone, A. Walne, H. Tamary, Y. Masunari, M. Kirwan, R. Beswick, T. Vulliamy, and I. Dokal
Telomerase reverse-transcriptase homozygous mutations in autosomal recessive dyskeratosis congenita and Hoyeraal-Hreidarsson syndrome
Blood,
December 15, 2007;
110(13):
4198 - 4205.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. K. Garcia, W. E. Wright, and J. W. Shay
Human diseases of telomerase dysfunction: insights into tissue aging
Nucleic Acids Res.,
December 3, 2007;
35(22):
7406 - 7416.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. Siegl-Cachedenier, I. Flores, P. Klatt, and M. A. Blasco
Telomerase reverses epidermal hair follicle stem cell defects and loss of long-term survival associated with critically short telomeres
J. Cell Biol.,
October 22, 2007;
179(2):
277 - 290.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Marrone, P. Sokhal, A. Walne, R. Beswick, M. Kirwan, S. Killick, M. Williams, J. Marsh, T. Vulliamy, and I. Dokal
Functional characterization of novel telomerase RNA (TERC) mutations in patients with diverse clinical and pathological presentations
Haematologica,
August 1, 2007;
92(8):
1013 - 1020.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Hsu, M. J. McEachern, A. T. Dandjinou, Y. Tzfati, E. Orr, E. H. Blackburn, and N. F. Lue
Telomerase core components protect Candida telomeres from aberrant overhang accumulation
PNAS,
July 10, 2007;
104(28):
11682 - 11687.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z.-T. Xin, A. D. Beauchamp, R. T. Calado, J. W. Bradford, J. A. Regal, A. Shenoy, Y. Liang, P. M. Lansdorp, N. S. Young, and H. Ly
Functional characterization of natural telomerase mutations found in patients with hematologic disorders
Blood,
January 15, 2007;
109(2):
524 - 532.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. B. Cantor and A. Shimamura
Cellular basis of hematopoiesis and marrow failure syndromes
ASH Self-Assessment Program,
January 1, 2007;
2007(1):
23 - 44.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. D. Mozdy and T. R. Cech
Low abundance of telomerase in yeast: Implications for telomerase haploinsufficiency
RNA,
September 1, 2006;
12(9):
1721 - 1737.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Jaras, A. Edqvist, J. Rebetz, L. G. Salford, B. Widegren, and X. Fan
Human short-term repopulating cells have enhanced telomerase reverse transcriptase expression
Blood,
August 1, 2006;
108(3):
1084 - 1091.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. J. Vulliamy, A. Marrone, S. W. Knight, A. Walne, P. J. Mason, and I. Dokal
Mutations in dyskeratosis congenita: their impact on telomere length and the diversity of clinical presentation
Blood,
April 1, 2006;
107(7):
2680 - 2685.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. E. Bilsland, K. Stevenson, S. Atkinson, W. Kolch, and W. N. Keith
Transcriptional Repression of Telomerase RNA Gene Expression by c-Jun-NH2-Kinase and Sp1/Sp3
Cancer Res.,
February 1, 2006;
66(3):
1363 - 1370.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Yamaguchi, R. T. Calado, H. Ly, S. Kajigaya, G. M. Baerlocher, S. J. Chanock, P. M. Lansdorp, and N. S. Young
Mutations in TERT, the Gene for Telomerase Reverse Transcriptase, in Aplastic Anemia
N. Engl. J. Med.,
April 7, 2005;
352(14):
1413 - 1424.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Ly, R. T. Calado, P. Allard, G. M. Baerlocher, P. M. Lansdorp, N. S. Young, and T. G. Parslow
Functional characterization of telomerase RNA variants found in patients with hematologic disorders
Blood,
March 15, 2005;
105(6):
2332 - 2339.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
