Letter abstract
Nature Genetics 41, 936 - 940 (2009)
Published online: 28 June 2009 | doi:10.1038/ng.405
Mutations affecting the secretory COPII coat component SEC23B cause congenital dyserythropoietic anemia type II
Klaus Schwarz1,2,14, Achille Iolascon3,14, Fatima Verissimo4, Nikolaus S Trede5,6, Wyatt Horsley5,6, Wen Chen7, Barry H Paw7, Karl-Peter Hopfner8, Karlheinz Holzmann9, Roberta Russo3, Maria Rosaria Esposito3, Daniela Spano3, Luigia De Falco3, Katja Heinrich1, Brigitte Joggerst4, Markus T Rojewski1,2, Silverio Perrotta10, Jonas Denecke11, Ulrich Pannicke1, Jean Delaunay12, Rainer Pepperkok4 & Hermann Heimpel13
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.
- Institute for Transfusion Medicine, University of Ulm, Ulm, Germany.
- Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service Baden-Wuerttemberg-Hessen, Ulm, Germany.
- Department of Biochemistry and Medical Biotechnologies, University Federico II of Naples and CEINGE Advanced Biotechnologies, Naples, Italy.
- Cell Biology and Biophysics, European Molecular Biology Laboratory, Heidelberg, Germany.
- Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.
- Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA.
- Department of Medicine, Hematology Division, Brigham & Women's Hospital, and Hematology-Oncology Division, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA.
- Center for Integrated Protein Science and Gene Center, Department of Chemistry and Biochemistry, Ludwig-Maximilians-University Munich, Munich, Germany.
- Chip Facility ZKF, University Hospital Ulm, Ulm, Germany.
- Department of Pediatrics, Second University of Naples, Naples, Italy.
- Department of Pediatrics, University of Rostock, Rostock, Germany.
- INSERM U 779, Hôpital de Bicêtre, 94275 Le Kremlin-Bicêtre, France.
- Department Internal Medicine III, University Hospital Ulm, Ulm, Germany.
- These authors contributed equally to this work.
Correspondence to: Klaus Schwarz1,2,14 e-mail: klaus.schwarz@uni-ulm.de
Correspondence to: Achille Iolascon3,14 e-mail: iolascon@ceinge.unina.it
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