Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

The gene encoding ribosomal protein S19 is mutated in Diamond-Blackfan anaemia

Abstract

Diamond–Blackfan anaemia (DBA) is a constitutional erythroblastopenia characterized by absent or decreased erythroid precursors. The disease, previously mapped to human chromosome 19q13, is frequently associated with a variety of malformations. To identify the gene involved in DBA, we cloned the chromosome 19q13 breakpoint in a patient with a reciprocal X;19 chromosome translocation. The breakpoint occurred in the gene encoding ribosomal protein S19. Furthermore, we identified mutations in RPS19 in 10 of 40 unrelated DBA patients, including nonsense, frameshift, splice site and missense mutations, as well as two intragenic deletions. These mutations are associated with clinical features that suggest a function for RPS19 in erythropoiesis and embryogenesis.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Identification of the chromosome 19 translocation breakpoint in the patient with t(X;19).
Figure 2: Map of the human RPS19 region.
Figure 3: Expression analysis of RPS19.
Figure 4: Identification of RPS19 mutations in Diamond–Blackfan anaemia patients.
Figure 5: Segregation of RPS19 mutations in families.
Figure 6: Alignment of RPS19 from human and other species.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Halperin, D.S. & Freedman, M.H. Diamond–Blackfan anemia: etiology, pathophysiology, and treatment. Am. J. Pediatr. Hematol. Oncol. 11, 380–394 ( 1989).

    CAS  PubMed  Google Scholar 

  2. Young, N.S. & Alter, B.P. Aplastic Anemia: Acquired and Inherited (WB Saunders, Philadelphia, 1994).

    Google Scholar 

  3. Diamond, L.K., Wang, W.C. & Alter, B.P. Congenital hypoplastic anemia. Adv. Pediatr. 22, 349–378 ( 1976).

    CAS  PubMed  Google Scholar 

  4. Ball, S.E., McGuckin, C.P., Jenkins, G. & Gordon–Smith, E.C. Diamond–Blackfan anemia in the UK: analysis of 80 cases from a 20–year birth cohort. Br. J. Haematol. 94, 645– 653 (1996).

    Article  CAS  Google Scholar 

  5. Janov, A.J., Leong, T., Nathan, D.G. & Guinan EC. Diamond–Blackfan anemia. Natural history and sequelae of treatment. Medicine 75, 77– 88 (1996).

    Article  CAS  Google Scholar 

  6. Gustavsson, P. et al. Diamond–Blackfan anaemia: genetic homogeneity for a gene on chromosome 19q13 restricted to 1.8 Mb. Nature Genet. 16, 368–371 (1997).

    Article  CAS  Google Scholar 

  7. Gustavsson, P. et al. Identification of microdeletions spanning the Diamond–Blackfan anemia (DBA) locus on 19q13 and evidence for genetic heterogeneity. Am. J. Hum. Genet. 63, 1388–1395 (1998).

    Article  CAS  Google Scholar 

  8. Mugishima, H. et al. Bone marrow transplantation for Diamond–Blackfan anemia. Bone Marrow Transplant. 15, 55– 58 (1995).

    CAS  PubMed  Google Scholar 

  9. Tsai, P.H., Arkin, S. & Lipton, J. An intrinsic progenitor defect in Diamond–Blackfan anemia. Br. J. Haematol. 73, 112– 120 (1989).

    Article  CAS  Google Scholar 

  10. Bagnara, G.P. et al. In vitro growth and regulation of bone marrow enriched CD34+ hematopoietic progenitors in Diamond–Blackfan anemia. Blood 78, 2203–2210 ( 1991).

    CAS  PubMed  Google Scholar 

  11. McGuckin, C.P., Ball, S.E. & Gordon–Smith, E.C. Diamond–Blackfan anaemia: three patterns of in vitro response to haemopoietic growth factors. Br. J. Haematol. 89, 457–464 ( 1995).

    Article  CAS  Google Scholar 

  12. Dianzani, I. et al. Mutations in the erythropoietin receptor gene are not a common cause of Diamond–Blackfan anemia. Blood 87, 2568–2572 (1996).

    CAS  PubMed  Google Scholar 

  13. Gustavsson, P. et al. Diamond–Blackfan anaemia in a girl with a de novo balanced reciprocal X;19 translocation. J. Med. Genet. 34, 779–782 (1997).

    Article  CAS  Google Scholar 

  14. Nishimura, D.Y. et al. The forkhead transcription factor gene FKHL7 is responsible for glaucoma phenotypes which map to 6p25. Nature Genet. 19, 140–147 (1998).

    Article  CAS  Google Scholar 

  15. Ashworth, L.K. et al. An integrated metric physical map of human chromosome 19. Nature Genet. 11, 422– 427 (1995).

    Article  CAS  Google Scholar 

  16. Kondoh, N., Schweinfest, C.W., Henderson, K.W. & Papas, T.S. Differential expression of S19 ribosomal protein, laminin–binding protein, and human lymphocyte antigen class I messenger RNAs associated with colon carcinoma progression and differentiation. Cancer Res. 52, 791–796 (1992).

    CAS  PubMed  Google Scholar 

  17. Hashimoto, S., Mohrenweiser, H.W., Gregersen, P.K. & Chiorazzi, N. Chromosomal localization, genomic structure, and allelic polymorphism of the human CD79α (Ig–α/mb–1) gene. Immunogenetics 40, 287–295 ( 1994).

    CAS  PubMed  Google Scholar 

  18. Hart, M.J. et al. Identification of a novel guanine nucleotide exchange factor for the Rho GTPase. J. Biol. Chem. 271, 25452–25458 (1996).

    Article  CAS  Google Scholar 

  19. Wool, I.G., Chan, Y.L. & Gluck, A. Mammalian ribosomes: the structure and the evolution of the proteins. in Translational Control (eds Hershey, J.W.B., Mathews, M.B. & Sonenberg, N.) 685–718 (Cold Spring Harbor Laboratory Press, New York, 1996).

    Google Scholar 

  20. Frigerio, J.M., Dagorn, J.C. & Iovanna, J.L. Cloning, sequencing and expression of the L5, L21, L27a, L28, S5, S9, S10 and S29 human ribosomal protein mRNAs. Biochim. Biophys. Acta 1262, 64–68 (1995).

    Article  Google Scholar 

  21. Brunak, S., Engelbrecht, J. & Knudsen, S. Prediction of human mRNA donor and acceptor sites from the DNA sequence. J. Mol. Biol. 220, 49– 65 (1991).

    Article  CAS  Google Scholar 

  22. Kenmochi, N. et al. A map of 75 human ribosomal protein genes. Genome Res. 8, 509–523 ( 1998).

    Article  CAS  Google Scholar 

  23. Wool, I.G. Extraribosomal functions of ribosomal proteins. in Ribosomal RNA and Group I Introns (eds Green, R. & Schroeder, R.) 153– 178 (R.G. Landes and Springer Company, New York, 1996 ).

  24. Fisher, E.M. et al. Homologous ribosomal protein genes on the human X and Y chromosomes: escape from X inactivation and possible implications for Turner syndrome. Cell 63, 1205–1218 (1990).

    Article  CAS  Google Scholar 

  25. Watanabe, M., Zinn, A.R., Page, D.C. & Nishimoto, T. Functional equivalence of human X– and Y–encoded isoforms of ribosomal protein S4 consistent with a role in Turner syndrome. Nature Genet. 4, 268–271 (1993).

    Article  CAS  Google Scholar 

  26. Heiss, N.S. et al. X–linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions. Nature Genet. 19, 32–38 (1998).

    Article  CAS  Google Scholar 

  27. Etter, A., Bernard, V., Kenzelmann, M., Tobler, H. & Müller, F. Ribosomal heterogeneity from chromatin diminuition in Ascaris lumbricoides. Science 265, 954–956.

  28. Cramton, S.E. & Laski F.A. String of pearls encodes Drosophila ribosomal protein S2, has Minute–like characteristics, and is required during oogenesis. Genetics 137, 1039–1048 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Watson, K.L., Konrad, K.D., Woods, D.F. & Bryant, P.J. Drosophila homolog of the human S6 ribosomal protein is required for tumor suppression in the hematopoietic system. Proc. Natl Acad. Sci. USA 89, 11302–11306 ( 1992).

    Article  CAS  Google Scholar 

  30. Hart, K., Klein, T. & Wilcox, M. A Minute encoding a ribosomal protein enhances wing morphogenesis mutants. Mech. Dev. 43, 101– 110 (1993).

    Article  CAS  Google Scholar 

  31. FlyBase. FlyBase: A Drosophila database. Nucleic Acids Res. 25, 63– 66 (1997).

  32. Meyuhas, O., Avni, D. & Shama, S. Translational control of ribosomal protein mRNAs in eukaryotes. in Translational Control (eds Hershey, J.W.B., Mathews, M.B. & Sonenberg, N.) 363–388 (Cold Spring Harbor Laboratory Press, New York, 1996).

    Google Scholar 

  33. Avni, D., Biberman, Y. & Meyuhas, O. The 5´ terminal oligopyrimidine tract confers translational control on TOP mRNAs in a cell type– and sequence context–dependent manner. Nucleic Acids Res. 25, 995– 1001 (1997).

    Article  CAS  Google Scholar 

  34. Willig, T.N., Ball, S.E. & Tchernia, G. Current concepts and issues in Diamond–Blackfan anemia. Curr. Opin. Hematol. 5, 109– 115 (1998).

    Article  CAS  Google Scholar 

  35. Andersson, B., Wentland, M.A., Ricafrente, J.Y., Liu, W. & Gibbs, R.A. A "double adaptor" method for improved shotgun library construction. Anal. Biochem. 236, 107–113 (1996).

    Article  CAS  Google Scholar 

  36. Andersson, B., Lu, J., Edwards, K.E., Muzny, D.M. & Gibbs, R.A. Method for 96–well M13 DNA template preparations for large–scale sequencing. Biotechniques 20, 1022–1027 (1996).

    Article  CAS  Google Scholar 

  37. Smith, L.M. et al. Fluorescence detection in automated DNA sequence analysis. Nature 321, 674–679 (1986).

    Article  CAS  Google Scholar 

  38. Staden, R. The Staden sequence analysis package. Mol. Biotechnol. 5, 233–241 (1996).

    Article  CAS  Google Scholar 

  39. Richards, S., Muzny, D.M., Civitello, A.B., Lu, F. & Gibbs, R.A. in Automated DNA Sequencing and Analysis Techniques (ed. Venter, J.C.) 191–197 (Academic Press, Orlando, 1994).

    Book  Google Scholar 

  40. Altschul, S.F., Gish, W., Miller, W., Myers, E.W. & Lipman, D.J. Basic local alignment search tool. J. Mol. Biol. 215, 403–410 ( 1990).

    Article  CAS  Google Scholar 

  41. Uberbacher, E.C. & Mural, R.J. Locating protein–coding regions in human DNA sequences by a multiple sensor–neural network approach. Proc. Natl Acad. Sci. USA 88, 11261– 11265 (1991).

    Article  CAS  Google Scholar 

  42. Chomczynski, P. & Sacchi, N. Single–step method of RNA isolation by acid guanidinium thiocyanate–phenol–chloroform extraction. Anal. Biochem. 162, 156– 159 (1987).

    Article  CAS  Google Scholar 

  43. Pettersson, M., Sundström, C., Nilsson, K. & Larsson, L.G. The hematopoetic transcription factor PU.1 is downregulated in human multiple myeloma cell lines. Blood 86, 2747– 2753 (1995).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to the patients and their families for their participation in this study. We thank O. Nygård and H. Johansson for discussions; L. Gordon for cosmids in the 19q13 region; and the European DBA consortium of the European Society for Pediatric Hematology and Immunology and the Resource Center of the German Human Genome Project, Berlin. This work was supported by grants from the Children's Cancer Foundation of Sweden, the Swedish Medical Research Council, the DBA Foundation Inc., T. and R. Söderbergs Fund, The Swedish Cancer Society, The Beijer Foundation, the Borgström Foundation, Ronald McDonalds fund, Lundbergs Foundation, Wera Ekström's fund, Uppsala University, Association Française Contre les Myopathies, Généthon and DRC (CRC 950183) AP–HP, Telethon Italia (grant E.619), NIH grants DK 32094 and DK 26263 and Max Reinhart Charitable Trust.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Niklas Dahl.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Draptchinskaia, N., Gustavsson, P., Andersson, B. et al. The gene encoding ribosomal protein S19 is mutated in Diamond-Blackfan anaemia. Nat Genet 21, 169–175 (1999). https://doi.org/10.1038/5951

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/5951

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing