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

Blood. 2011 Jun 23;117(25):6928-38. doi: 10.1182/blood-2010-09-308478. Epub 2011 Mar 1.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • CDAN1 protein, human
  • Carrier Proteins
  • Chromatin
  • Chromosomal Proteins, Non-Histone
  • Glycoproteins
  • Nuclear Proteins
  • SEC23B protein, human
  • Vesicular Transport Proteins
  • codanin-1 protein, mouse
  • heterochromatin-specific nonhistone chromosomal protein HP-1