Codanin-1 mutations in congenital dyserythropoietic anemia type 1 affect HP1{alpha} localization in erythroblasts.

Abstract

Congenital dyserythropoietic anemia type 1 (CDA-1), a rare inborn anemia characterized by abnormal chromatin ultrastructure in erythroblasts, is caused by abnormalities in codanin-1, a highly conserved protein of unknown function. We have produced 3 monoclonal antibodies to codanin-1 that demonstrate its distribution in both nucleus and cytoplasm by immunofluorescence and allow quantitative measurements of patient and normal material by Western blot. A detailed analysis of chromatin structure in CDA-1 erythroblasts shows no abnormalities in overall histone composition, and the genome-wide epigenetic landscape of several histone modifications is maintained. However, immunofluorescence analysis of intermediate erythroblasts from patients with CDA-1 reveals abnormal accumulation of HP1α in the Golgi apparatus. A link between mutant codanin-1 and the aberrant localization of HP1α is supported by the finding that codanin-1 can be coimmunoprecipitated by anti-HP1α antibodies. Furthermore, we show colocalization of codanin-1 with Sec23B, the protein defective in CDA-2 suggesting that the CDAs might be linked at the molecular level. Mice containing a gene-trapped Cdan1 locus demonstrate its widespread expression during development. Cdan1(gt/gt) homozygotes die in utero before the onset of primitive erythropoiesis, suggesting that Cdan1 has other critical roles during embryogenesis.

• Authors: Raffaele Renella, Nigel A Roberts, Jill M Brown, Marco De Gobbi, Louise E Bird, Tasneem Hassanali, Jacqueline A Sharpe, Jacqueline Sloane-Stanley, David J P Ferguson, Jacqueline Cordell, Veronica J Buckle, Douglas R Higgs, William G Wood
• Journal: Blood (Blood) Vol. 117 Issue 25 Pg. 6928-38 (Jun 23 2011) ISSN: 1528-0020 [Electronic] United States
• PMID: 21364188 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CBX5 protein, human
• CDAN1 protein, human
• Carrier Proteins
• Chromatin
• Chromosomal Proteins, Non-Histone
• Glycoproteins
• Nuclear Proteins
• SEC23B protein, human
• Vesicular Transport Proteins
• codanin-1 protein, mouse
• Chromobox Protein Homolog 5

Topics

• Anemia, Dyserythropoietic, Congenital (genetics, pathology)
• Animals
• Carrier Proteins (genetics)
• Cell Line, Tumor
• Cells, Cultured
• Chromatin (pathology)
• Chromobox Protein Homolog 5
• Chromosomal Proteins, Non-Histone (analysis)
• Erythroblasts (metabolism, pathology)
• Female
• Glycoproteins (analysis, genetics)
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Mutation
• Nuclear Proteins
• Vesicular Transport Proteins (analysis)