The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita (original) (raw)

Nature volume 413, pages 432–435 (2001)Cite this article

Abstract

Dyskeratosis congenita is a progressive bone-marrow failure syndrome that is characterized by abnormal skin pigmentation, leukoplakia and nail dystrophy1,2. X-linked, autosomal recessive and autosomal dominant inheritance have been found in different pedigrees. The X-linked form of the disease is due to mutations in the gene DKC1 in band 2, sub-band 8 of the long arm of the X chromosome (ref. 3). The affected protein, dyskerin, is a nucleolar protein that is found associated with the H/ACA class of small nucleolar RNAs and is involved in pseudo-uridylation of specific residues of ribosomal RNA4. Dyskerin is also associated with telomerase RNA (hTR)5, which contains a H/ACA consensus sequence6,7. Here we map the gene responsible for dyskeratosis congenita in a large pedigree with autosomal dominant inheritance. Affected members of this family have an 821-base-pair deletion on chromosome 3q that removes the 3′ 74 bases of hTR. Mutations in hTR were found in two other families with autosomal dominant dyskeratosis congenita.

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Acknowledgements

We thank B. Alter and E. Gluckman for facilitating recruitment to the dyskeratosis congenita registry, and the dyskeratosis congenita families and their clinicians who provided us with the samples. We also thank Z. Amoura, R. Gruppo and J. Miller. We thank D. Stevens for technical assistance and D. Smyth for help with the linkage. We are grateful to S. Knight, W. Watkins, J. Clarke, J. O'Donnel and S. Reiss for help and discussions, and J. Goldman and L. Luzzatto for their continued support of the dyskeratosis congenita project. The genome screen was performed at the Linkage Hotel MRC UK HGMP Resource Centre. This work was supported by the Wellcome Trust.

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Authors and Affiliations

  1. Department of Haematology, Division of Investigative Science, Faculty of Medicine, Imperial College School of Science, Technology and Medicine, Hammersmith Hospital, Ducane Road, London, W12 ONN, UK
    Tom Vulliamy, Anna Marrone, Philip J. Mason & Inderjeet Dokal
  2. Department of Pediatrics, The University of Iowa Hospitals and Clinics, Iowa City, 52242-1083, Iowa, USA
    Frederick Goldman
  3. MRC UK, HGMP Resource Centre, Hinxton Cambridge, CB10 1SB, UK
    Andrew Dearlove
  4. Division of Hematology, Washington University School of Medicine, St. Louis, 63110, Missouri, USA
    Monica Bessler

Authors

  1. Tom Vulliamy
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  2. Anna Marrone
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  3. Frederick Goldman
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  4. Andrew Dearlove
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  5. Monica Bessler
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  6. Philip J. Mason
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  7. Inderjeet Dokal
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Corresponding author

Correspondence toPhilip J. Mason.

Supplementary information

Figure S1

(GIF 31.8 KB)

Family DCR101. Localisation of the gene responsible for autosomal dominant DC to chromosome 3q was achieved through a genome wide screen of 400 microsatellite markers, initially using 6 affected (II:3, II:6, II:12, II:15, III:4 and III:8) and 2 unaffected (II:4 and II:10) individuals from this pedigree. Linkage was observed to the markers in the boxed haplotype, with a maximal LOD score of 1.8 being obtained with the marker D3S3725. Shaded individuals were either too young for diagnosis or showed features that were suggestive but not diagnostic of DC. Affected individuals are shown in black, normal individuals in white. The haplotype segregating with the disease is boxed in all individuals carrying the hTR deletion.

SI Table. Phenotype of DC patients and mTR -/- mice

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Vulliamy, T., Marrone, A., Goldman, F. et al. The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita.Nature 413, 432–435 (2001). https://doi.org/10.1038/35096585

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