Abstract
Dyskeratosis congenita (DC) is a rare multisystem bone marrow failure syndrome that displays marked clinical and genetic heterogeneity. X-linked recessive, autosomal dominant and autosomal recessive forms of the disease are recognized. The gene that is mutated in the X-linked form of the disease is DKC1. The DKC1 -encoded protein, dyskerin, is a component of small nucleolar ribonucleoprotein particles, which are important in ribosomal RNA processing, and of the telomerase complex. The autosomal dominant form of DC is due to mutations in the gene for the RNA component of telomerase (TERC). Because both dyskerin and TERC are components of the telomerase complex and all patients with DC have short telomeres, the principal pathology of DC appears to relate to telomerase dysfunction, although defects in ribosomal processing via dyskerin’s involvement in pseudouridylation cannot be completely ruled out. The gene or genes involved in autosomal recessive DC remain elusive, although genes whose products are required for telomere maintenance remain strong candidates. The study of DC highlights the importance of telomerase in humans and how its deficiency results in multiple abnormalities, including premature aging, bone marrow failure, and cancer.
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References
Broccoli D. Function, replication and structure of the mammalian telomere. Cytotechnology. 2004;45:3–12.
Blackburn EH. The end of the (DNA) line. Nat Struct Biol. 2000;7:847–850.
Cong YS, Wright WE, Shay JW. Human telomerase and its regulation. Microbiol Mol Biol Rev. 2002;66:407–425.
De Lange T. Protection of mammalian telomeres. Oncogene. 2002;21:532–540.
Autexier C, Greider CW. Functional reconstitution of wild-type and mutant Tetrahymena telomerase. Genes Dev. 1994;8:563–575.
Pogacic V, Dragon F, Filipowicz W. Human H/ACA small nucleolar RNPs and telomerase share evolutionarily conserved proteins NHP2 and NOP10. Mol Cell Biol. 2000;20:9028–9040.
Dragon F, Pogacic V, Filipowicz W. In vitro assembly of human H/ACA small nucleolar RNPs reveals unique features of U17 and telomerase RNAs. Mol Cell Biol. 2000;20:3037–3048.
Karlseder J. Telomere repeat binding factors: keeping the ends in check. Cancer Lett. 2003;194:189–197.
Masutomi K, Yu EY, Khurts S, et al. Telomerase maintains telomere structure in normal human cells. Cell. 2003;114:241–253.
Wong JM, Collins K. Telomere maintenance and disease. Lancet. 2003;362:983–988.
Colgin LM, Reddel RR. Telomere maintenance mechanisms and cellular immortalization. Curr Opin Genet Dev. 1999;9:97–103.
Broccoli D, Young JW, de Lange T. Telomerase activity in normal and malignant hematopoietic cells. Proc NatlAcad Sci USA. 1995;92:9082–9086.
Chiu CP, Dragowska W, Kim NW, et al. Differential expression of telomerase activity in hematopoietic progenitors from adult human bone marrow. Stem Cells. 1996;14:239–248.
Harle-Bachor C, Boukamp P. Telomerase activity in the regenerative basal layer of the epidermis in human skin and in immortal and carcinoma-derived skin keratinocytes. Proc Natl Acad Sci USA. 1996;93:6476–6481.
Yasumoto S, Kunimura C, Kikuchi K, et al. Telomerase activity in normal human epithelial cells. Oncogene. 1996;13:433–439.
Zinsser F. Atropha cutis reticularis cum pigmentatione, dystrophia ungium et leukoplakia oris. Ikonogr Dermatol (Hyoto). 1906;5:219–223.
Engman MF. A unique case of reticular pigmentation of the skin with atrophy. Arch Dermatol Syph. 1926;13:685–687.
Cole HN, Rauschkolb JC, Toomey J. Dyskeratosis congenita with pigmentation, dystrophia unguis and leukokeratosis oris. Arch Dermatol Syph. 1930;21:71–95.
Sirinavin C, Trowbridge AA. Dyskeratosis congenita: clinical features and genetic aspects: report of a family and review of the literature. J Med Genet. 1975;12:339–354.
Drachtman RA, Alter BP. Dyskeratosis congenita. Dermatol Clin. 1995;13:33–39.
Knight S, Vulliamy T, Copplestone A, Gluckman E, Mason P, Dokal I. Dyskeratosis Congenita (DC) Registry: identification of new features of DC. Br J Haematol. 1998;103:990–996.
Dokal I. Dyskeratosis congenita in all its forms. Br J Haematol. 2000;110:768–779.
Heiss NS, Knight SW, Vulliamy TJ, et al. X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions. Nat Genet. 1998;19:32–38.
Vulliamy T, Marrone A, Goldman F, et al. The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita. Nature. 2001;413:432–435.
Meier UT, Blobel G. NAP57, a mammalian nucleolar protein with a putative homolog in yeast and bacteria. J Cell Biol. 1994;127:1505–1514.
Tollervey D, Kiss T. Function and synthesis of small nucleolar RNAs. Curr Opin Cell Biol. 1997;9:337–342.
Filipowicz W, Pogacic V. Biogenesis of small nucleolar ribonucleo-proteins. Curr Opin Cell Biol. 2002;14:319–327.
Lafontaine DL, Bousquet-Antonelli C, Henry Y, Caizergues-Ferrer M, Tollervey D. The box H+ACA snoRNAs carry Cbf5p, the putative rRNA pseudouridine synthase. Genes Dev. 1998;12:527–537.
Zebarjadian Y, King T, Fournier MJ, Clarke L, Carbon J. Point mutations in yeast CBF5 can abolish in vivo pseudouridylation of rRNA. Mol Cell Biol. 1999;19:7461–7472.
Henras A, Henry Y, Bousquet-Antonelli C, Noaillac-Depeyre J, Gelugne JP, Caizergues-Ferrer M. Nhp2p and Nop10p are essential for the function of H/ACA snoRNPs. EMBO J. 1998;17:7078–7090.
Henras AK, Capeyrou R, Henry Y, Caizergues-Ferrer M. Cbf5p, the putative pseudouridine synthase of H/ACA-type snoRNPs, can form a complex with Gar1p and Nop10p in absence of Nhp2p and box H/ACA snoRNAs. RNA. 2004;10:1704–1712.
Wang C, Meier UT. Architecture and assembly of mammalian H/ACA small nucleolar and telomerase ribonucleoproteins. EMBO J. 2004;23:1857–1867.
Meier UT. The many facets of H/ACA ribonucleoproteins. Chro-mosoma. 2005;114:1–14.
Luzzatto L, Karadimitris A. Dyskeratosis and ribosomal rebellion. Nat Genet. 1998;19:6–7.
Mitchell JR, Wood E, Collins K. A telomerase component is defective in the human disease dyskeratosis congenita. Nature. 1999;402:551–555.
Mitchell JR, Cheng J, Collins K. A box H/ACA small nucleolar RNA-like domain at the human telomerase RNA 3′ end. Mol Cell Biol. 1999;19:567–576.
Vulliamy TJ, Knight SW, Mason PJ, Dokal I. Very short telomeres in the peripheral blood of patients with X-linked and autosomal dyskeratosis congenita. Blood Cells Mol Dis. 2001;27:353–357.
Mochizuki Y, He J, Kulkarni S, Bessler M, Mason PJ. Mouse dyskerin mutations affect accumulation of telomerase RNA and small nucleolar RNA, telomerase activity, and ribosomal RNA processing. Proc NatlAcad Sci USA. 2004;101:10756–10761.
Marrone A, Dokal I. Dyskeratosis congenita: molecular insights into telomerase function, ageing and cancer. Expert Rev Mol Med. 2004;6:1–23.
Kanegane H, Kasahara Y, Okamura J, et al. Identification of DKC1 gene mutations in Japanese patients with X-linked dyskeratosis congenita. Br J Haematol. 2005;129:432–434.
Knight SW, Heiss NS, Vulliamy TJ, et al. X-linked dyskeratosis congenita is predominantly caused by missense mutations in the DKC1 gene. Am J Hum Genet. 1999;65:50–58.
Zucchini C, Strippoli P, Biolchi A, et al. The human TruB family of pseudouridine synthase genes, including the Dyskeratosis Congenita 1 gene and the novel member TRUB1. Int J Mol Med. 2003;11:697–704.
Ramamurthy V, Swann SL, Paulson JL, Spedaliere CJ, Mueller EG. Critical aspartic acid residues in pseudouridine synthases. J Biol Chem. 1999;274:22225–22230.
Knight SW, Vulliamy TJ, Morgan B, Devriendt K, Mason PJ, Dokal I. Identification of novel DKC1 mutations in patients with dyskeratosis congenita: implications for pathophysiology and diagnosis. Hum Genet. 2001;108:299–303.
Fu D, Collins K. Distinct biogenesis pathways for human telomerase RNA and H/ACA small nucleolar RNAs. Mol Cell. 2003;11:1361–1372.
Ren X, Gavory G, Li H, Ying L, Klenerman D, Balasubramanian S. Identification of a new RNA·RNA interaction site for human telomerase RNA (hTR): structural implications for hTR accumulation and a dyskeratosis congenita point mutation. Nucleic Acids Res. 2003;31:6509–6515.
Ueda CT, Roberts RW. Analysis of a long-range interaction between conserved domains of human telomerase RNA. RNA. 2004;10:139–147.
Keppler BR, Jarstfer MB. Inhibition of telomerase activity by preventing proper assemblage. Biochemistry. 2004;43:334–343.
Marrone A, Stevens D, Vulliamy T, Dokal I, Mason PJ. Heterozygous telomerase RNA mutations found in dyskeratosis congenita and aplastic anemia reduce telomerase activity via haploinsuffi-ciency. Blood. 2004;104:3936–3942.
Cerone MA, Ward RJ, Londono-Vallejo JA, Autexier C. Telomerase RNA mutated in autosomal dyskeratosis congenita reconstitutes a weakly active telomerase enzyme defective in telomere elongation. Cell Cycle. 2005;4:585–589.
Yeo M, Rha SY, Jeung HC, et al. Different role of functional domains of hTR in DNA binding to telomere and telomerase reconstruction. FEBS Lett. 2005;579:127–132.
Yingling YG, Shapiro BA. Dynamic behaviour of the telomerase RNA hairpin structure and its relationship to dyskeratosis congenita. J Mol Biol. 2005;348:27–42.
Vulliamy T, Marrone A, Szydlo R, Walne A, Mason PJ, Dokal I. Disease anticipation is associated with progressive telomere shortening in families with dyskeratosis congenita due to mutations in TERC. Nat Genet. 2004;36:447–449.
Shay JW, Wright WE. Telomeres in dyskeratosis congenita. Nat Genet. 2004;36:437–438.
Ball SE, Gibson FM, Rizzo S, Tooze JA, Marsh JC, Gordon-Smith EC. Progressive telomere shortening in aplastic anemia. Blood. 1998;91:3582–3592.
Brummendorf TH, Maciejewski JP, Mak J, Young NS, Lansdorp PM. Telomere length in leukocyte subpopulations of patients with aplastic anemia. Blood. 2001;97:895–900.
Karadimitris A, Araten DJ, Luzzatto L, Notaro R. Severe telomere shortening in patients with paroxysmal nocturnal hemoglobinuria affects both GPI- and GPI+ hematopoiesis. Blood. 2003;102:514–516.
Vulliamy T, Marrone A, Dokal I, Mason PJ. Association between aplastic anaemia and mutations in telomerase RNA. Lancet. 2002;359:2168–2170.
Fogarty PF, Yamaguchi H, Wiestner A, et al. Late presentation of dyskeratosis congenita as apparently acquired aplastic anaemia due to mutations in telomerase RNA. Lancet. 2003;362:1628–1630.
Yamaguchi H, Baerlocher GM, Lansdorp PM, et al. Mutations of the human telomerase RNA gene (TERC) in aplastic anemia and myelodysplastic syndrome. Blood. 2003;102:916–918.
Keith WN, Vulliamy T, Zhao J, et al. A mutation in a functional Sp1 binding site of the telomerase RNA gene (hTERC) promoter in a patient with paroxysmal nocturnal haemoglobinuria. BMC Blood Disord. 2004;4:3.
Knight SW, Heiss NS, Vulliamy TJ, et al. Unexplained aplastic anaemia, immunodeficiency, and cerebellar hypoplasia (Hoyeraal- Hreidarsson syndrome) due to mutations in the dyskeratosis congenita gene, DKC1. Br J Haematol. 1999;107:335–339.
Yaghmai R, Kimyai-Asadi A, Rostamiani K, et al. Overlap of dyskeratosis congenita with the Hoyeraal-Hreidarsson syndrome. J Pediatr. 2000;136:390–393.
Vulliamy TJ, Walne A, Baskaradas A, Mason PJ, Marrone A, Dokal I. Mutations in the reverse transcriptase component of telomerase (TERT) in patients with bone marrow failure. Blood Cells Mol Dis. 2005;34:257–263.
Yamaguchi H, Calado RT, Ly H, et al. Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N Engl J Med. 2005;352:1413–1424.
Holt SE, Aisner DL, Baur J, et al. Functional requirement of p23 and Hsp90 in telomerase complexes. Genes Dev. 1999;13:817–826.
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Walne, A.J., Marrone, A. & Dokal, I. Dyskeratosis Congenita: A Disorder of Defective Telomere Maintenance?. Int J Hematol 82, 184–189 (2005). https://doi.org/10.1532/IJH97.05067
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DOI: https://doi.org/10.1532/IJH97.05067