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.

  • Letter
  • Published:

Mutations affecting the secretory COPII coat component SEC23B cause congenital dyserythropoietic anemia type II

Nature Genetics volume 41, pages 936–940 (2009)Cite this article

Abstract

Congenital dyserythropoietic anemias (CDAs) are phenotypically and genotypically heterogeneous diseases1,2,3,4. CDA type II (CDAII) is the most frequent CDA. It is characterized by ineffective erythropoiesis and by the presence of bi- and multinucleated erythroblasts in bone marrow, with nuclei of equal size and DNA content, suggesting a cytokinesis disturbance5. Other features of the peripheral red blood cells are protein and lipid dysglycosylation and endoplasmic reticulum double-membrane remnants4,6. Development of other hematopoietic lineages is normal. Individuals with CDAII show progressive splenomegaly, gallstones and iron overload potentially with liver cirrhosis or cardiac failure. Here we show that the gene encoding the secretory COPII component SEC23B is mutated in CDAII. Short hairpin RNA (shRNA)-mediated suppression of SEC23B expression recapitulates the cytokinesis defect. Knockdown of zebrafish sec23b also leads to aberrant erythrocyte development. Our results provide in vivo evidence for SEC23B selectivity in erythroid differentiation and show that SEC23A and SEC23B, although highly related paralogous secretory COPII components, are nonredundant in erythrocyte maturation.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: SEC23B mutation analysis.
Figure 2: SEC23B expression and function in erythroid cells.
Figure 3: Analysis of sec23b zebrafish morphants.

Similar content being viewed by others

Accession codes

Accessions

NCBI Reference Sequence

Protein Data Bank

References

  1. Heimpel, H. & Wendt, F. Congenital dyserythropoietic anemia with karyorrhexis and multinuclearity of erythroblasts. Helv. Med. Acta 34, 103–115 (1968).

    CAS  PubMed  Google Scholar 

  2. Wickramasinghe, S.N. Congenital dyserythropoietic anemias. Curr. Opin. Hematol. 7, 71–78 (2000).

    Article  CAS  Google Scholar 

  3. Iolascon, A. Congenital dyserythropoietic anemias: a still unsolved puzzle. Haematologica 85, 673–674 (2000).

    CAS  PubMed  Google Scholar 

  4. Heimpel, H. & Iolascon, A. in Disorders of Homeostasis, Erythrocytes, Erythropoiesis. 1st edn (eds. Beaumont, C., Beris, P., Beuzard, Y. & Brugnara, C.) Congenital dyserythropoietic anemia 120–142 (European School of Haematology, Paris, 2006).

    Google Scholar 

  5. Queisser, W., Spiertz, E., Jost, E. & Heimpel, H. Proliferation disturbances of erythroblasts in congenital dyserythropoietic anemia type I and II. Acta Haematol. 45, 65–76 (1971).

    Article  CAS  Google Scholar 

  6. Iolascon, A. et al. Congenital dyserythropoietic anemia type II: molecular basis and clinical aspects. Haematologica 81, 543–559 (1996).

    CAS  PubMed  Google Scholar 

  7. Heimpel, H. et al. Congenital dyserythropoietic anemia type II: epidemiology, clinical appearance, and prognosis based on long-term observation. Blood 102, 4576–4581 (2003).

    Article  CAS  Google Scholar 

  8. Gasparini, P. et al. Localization of the congenital dyserythropoietic anemia II locus to chromosome 20q11.2 by genomewide search. Am. J. Hum. Genet. 61, 1112–1116 (1997).

    Article  CAS  Google Scholar 

  9. Denecke, J. & Marquardt, T. Congenital dyserythropoietic anemia type II (CDAII/HEMPAS): Where are we now? Biochim. Biophys. Acta advance online publication doi:10.1016/j.bbadis.2008.12.005 (25 December 2008).

  10. Denecke, J. et al. Characterization of the N-glycosylation phenotype of erythrocyte membrane proteins in congenital dyserythropoietic anemia type II (CDA II/HEMPAS). Glycoconj. J. 25, 375–382 (2008).

    Article  CAS  Google Scholar 

  11. Lee, M.C., Miller, E.A., Goldberg, J., Orci, L. & Schekman, R. Bi-directional protein transport between the ER and Golgi. Annu. Rev. Cell Dev. Biol. 20, 87–123 (2004).

    Article  CAS  Google Scholar 

  12. Fromme, J.C., Orci, L. & Schekman, R. Coordination of COPII vesicle trafficking by Sec23. Trends Cell Biol. 18, 330–336 (2008).

    Article  CAS  Google Scholar 

  13. Cai, H., Reinisch, K. & Ferro-Novick, S. Coats, tethers, Rabs, and SNAREs work together to mediate the intracellular destination of a transport vesicle. Dev. Cell 12, 671–682 (2007).

    Article  CAS  Google Scholar 

  14. Ishihara, N. et al. Autophagosome requires specific early Sec proteins for its formation and NSF/SNARE for vacuolar fusion. Mol. Biol. Cell 12, 3690–3702 (2001).

    Article  CAS  Google Scholar 

  15. Penalver, E., Lucero, P., Moreno, E. & Lagunas, R. Clathrin and two components of the COPII complex, Sec23p and Sec24p, could be involved in endocytosis of the Saccharomyces cerevisiae maltose transporter. J. Bacteriol. 181, 2555–2563 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Mancias, J.D. & Goldberg, J. The transport signal on Sec22 for packaging into COPII-coated vesicles is a conformational epitope. Mol. Cell 26, 403–414 (2007).

    Article  CAS  Google Scholar 

  17. Fromme, J.C. et al. The genetic basis of a craniofacial disease provides insight into COPII coat assembly. Dev. Cell 13, 623–634 (2007).

    Article  CAS  Google Scholar 

  18. Lang, M.R., Lapierre, L.A., Frotscher, M., Goldenring, J.R. & Knapik, E.W. Secretory COPII coat component Sec23a is essential for craniofacial chondrocyte maturation. Nat. Genet. 38, 1198–1203 (2006).

    Article  CAS  Google Scholar 

  19. Rhodes, J. et al. Interplay of pu.1 and gata1 determines myelo-erythroid progenitor cell fate in zebrafish. Dev. Cell 8, 97–108 (2005).

    Article  CAS  Google Scholar 

  20. Boyadjiev, S.A. et al. Cranio-lenticulo-sutural dysplasia is caused by a SEC23A mutation leading to abnormal endoplasmic-reticulum-to-Golgi trafficking. Nat. Genet. 38, 1192–1197 (2006).

    Article  CAS  Google Scholar 

  21. Skop, A.R., Liu, H., Yates, J. III., Meyer, B.J. & Heald, R. Dissection of the mammalian midbody proteome reveals conserved cytokinesis mechanisms. Science 305, 61–66 (2004).

    Article  CAS  Google Scholar 

  22. Jones, B. et al. Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption disorders. Nat. Genet. 34, 29–31 (2003).

    Article  CAS  Google Scholar 

  23. Bi, X., Corpina, R.A. & Goldberg, J. Structure of the Sec23/24-Sar1 pre-budding complex of the COPII vesicle coat. Nature 419, 271–277 (2002).

    Article  CAS  Google Scholar 

  24. Mossessova, E., Bickford, L.C. & Goldberg, J. SNARE selectivity of the COPII coat. Cell 114, 483–495 (2003).

    Article  CAS  Google Scholar 

  25. Bi, X., Mancias, J.D. & Goldberg, J. Insights into COPII coat nucleation from the structure of Sec23.Sar1 complexed with the active fragment of Sec31. Dev. Cell 13, 635–645 (2007).

    Article  CAS  Google Scholar 

  26. Crookston, J.H., Crookston, M.C. & Rosse, W.F. Red-cell abnormalities in HEMPAS (hereditary erythroblastic multinuclearity with a positive acidified-serum test). Br. J. Haematol. 23 (Suppl.), 83–91 (1972).

    Article  Google Scholar 

  27. Ronzoni, L. et al. Erythroid differentiation and maturation from peripheral CD34+ cells in liquid culture: cellular and molecular characterization. Blood Cells Mol. Dis. 40, 148–155 (2008).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  29. Livak, K.J. & Schmitteng, T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(−ΔΔC(T)). Methods 25, 402–408 (2001).

    Article  CAS  Google Scholar 

  30. Paw, B.H. et al. Cell-specific mitotic defect and dyserythropoiesis associated with erythroid band3 deficiency. Nat. Genet. 34, 59–64 (2003).

    Article  CAS  Google Scholar 

  31. Eswar, N., Eramian, D., Webb, B., Shen, M.Y. & Sali, A. Protein structure modeling with MODELLER. Methods Mol. Biol. 426, 145–159 (2008).

    Article  CAS  Google Scholar 

  32. Pepperkok, R. et al. Beta-COP is essential for biosynthetic membrane transport from the endoplasmic reticulum to the Golgi complex in vivo. Cell 74, 71–82 (1993).

    Article  CAS  Google Scholar 

  33. Keller, P., Toomre, D., Diaz, E., White, J. & Simons, K. Multicolour imaging of post-Golgi sorting and trafficking in live cells. Nat. Cell Biol. 3, 140–149 (2001).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We acknowledge the technical assistance of S. Braun, I. Janz, T. Kersten, G. Baur, T. Becker and R. Leichtle. Anti-ts-O45-G monoclonal antibody 'VG' was a gift from K. Simons (Max Planck Institute of Molecular Cell Biology and Genetics). HeLa-Kyoto cells (human cervix carcinoma cells) were from S. Narumiya (Kyoto University) and T. Hirota (Institute of Molecular Pathology). These studies were supported by the German Red Cross Blood Service Baden-Wuerttemberg-Hessen to K.S., by the University of Ulm to H.H. and by the Else Kröner Fresenius Stiftung to K.S. and H.H. Additional support was provided by the Italian Ministero dell'Università e della Ricerca, by Telethon (Italy), by grants MUR-P35/126/IND and by grants Convenzione CEINGE-Regione Campania-Ass. Sanità to A.I. University of Utah Core facilities were supported by an US National Institutes of Health grant. K.-P.H. acknowledges support from the Deutsche Forschungsgemeinschaft (SFB 684). We thank the DIM Facility for imaging microscopy and the Flow Cytometry Facility for cell cycle analyses at CEINGE Institute.

Author information

Author notes

  1. Klaus Schwarz and Achille Iolascon: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute for Transfusion Medicine, University of Ulm, Ulm, Germany

    Klaus Schwarz, Katja Heinrich, Markus T Rojewski & Ulrich Pannicke

  2. Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service Baden-Wuerttemberg-Hessen, Ulm, Germany

    Klaus Schwarz & Markus T Rojewski

  3. Department of Biochemistry and Medical Biotechnologies, University Federico II of Naples and CEINGE Advanced Biotechnologies, Naples, Italy

    Achille Iolascon, Roberta Russo, Maria Rosaria Esposito, Daniela Spano & Luigia De Falco

  4. Cell Biology and Biophysics, European Molecular Biology Laboratory, Heidelberg, Germany

    Fatima Verissimo, Brigitte Joggerst & Rainer Pepperkok

  5. Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA

    Nikolaus S Trede & Wyatt Horsley

  6. Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA

    Nikolaus S Trede & Wyatt Horsley

  7. Department of Medicine, Hematology Division, and Hematology-Oncology Division, Brigham & Women's Hospital, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA

    Wen Chen & Barry H Paw

  8. Department of Chemistry and Biochemistry, Center for Integrated Protein Science and Gene Center, Ludwig-Maximilians-University Munich, Munich, Germany

    Karl-Peter Hopfner

  9. Chip Facility ZKF, University Hospital Ulm, Ulm, Germany

    Karlheinz Holzmann

  10. Department of Pediatrics, Second University of Naples, Naples, Italy

    Silverio Perrotta

  11. Department of Pediatrics, University of Rostock, Rostock, Germany

    Jonas Denecke

  12. INSERM U 779, Hôpital de Bicêtre, 94275 Le Kremlin-Bicêtre, France

    Jean Delaunay

  13. Department Internal Medicine III, University Hospital Ulm, Ulm, Germany

    Hermann Heimpel

Authors
  1. Klaus Schwarz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Achille Iolascon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fatima Verissimo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nikolaus S Trede
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wyatt Horsley
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wen Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Barry H Paw
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Karl-Peter Hopfner
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Karlheinz Holzmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Roberta Russo
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Maria Rosaria Esposito
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Daniela Spano
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Luigia De Falco
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Katja Heinrich
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Brigitte Joggerst
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Markus T Rojewski
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Silverio Perrotta
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Jonas Denecke
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Ulrich Pannicke
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Jean Delaunay
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Rainer Pepperkok
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Hermann Heimpel
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

K.S., A.I. and H.H. designed the study. H.H., A.I., S.P. and J. Delaunay treated subjects, collected clinical data and, together with J. Denecke, performed clinical laboratory analyses. K. Holzmann performed and K. Holzmann and K.S. analyzed the chip experiments. K.S., F.V., R.R., M.R.E., D.S., L.D.F., K. Heinrich, B.J., U.P. and R.P. performed the molecular, protein and cell analyses. K.-P.H. modeled the SEC23B structure. N.S.T. and W.H. performed zebrafish morpholino injections, blood cell preparations and electron microscopy. W.C. and B.H.P. performed the zebrafish western blot analysis. M.T.R. did the FACS analyses and fibroblast differentiation. K.S., A.I. and H.H. wrote the paper.

Corresponding authors

Correspondence to Klaus Schwarz or Achille Iolascon.

Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Tables 1–5 and Supplementary Figures 1 and 2 (PDF 2315 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schwarz, K., Iolascon, A., Verissimo, F. et al. Mutations affecting the secretory COPII coat component SEC23B cause congenital dyserythropoietic anemia type II. Nat Genet 41, 936–940 (2009). https://doi.org/10.1038/ng.405

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.405

This article is cited by

Search

Advanced 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