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

Journal article

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: Renella, R; Roberts, N; Brown, J; De Gobbi, M; Bird, L

• Journal: Blood
• Volume: 117
• Issue: 25
• Pages: 6928-6938
• Publication date: 2011-06-01
• DOI: 10.1182/blood-2010-09-308478
• EISSN: 1528-0020
• ISSN: 0006-4971
• Language: English
• Keywords: Humans; Glycoproteins; Mice; Female; Carrier Proteins; Vesicular Transport Proteins; Mutation; Male; Cell Line, Tumor; Mice, Inbred C57BL; Animals; Erythroblasts; Chromosomal Proteins, Non-Histone; Chromatin; Anemia, Dyserythropoietic, Congenital; Cells, Cultured