title: 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.affiliation: Medical Research Council Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK. raffaele.renella@childrens.harvard.edu
authors.forename: Raffaele
authors.initials: R
authors.lastname: Renella
authors.forename: Nigel A
authors.initials: NA
authors.lastname: Roberts
authors.forename: Jill M
authors.initials: JM
authors.lastname: Brown
authors.forename: Marco
authors.initials: M
authors.lastname: De Gobbi
authors.forename: Louise E
authors.initials: LE
authors.lastname: Bird
authors.forename: Tasneem
authors.initials: T
authors.lastname: Hassanali
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Sharpe
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Sloane-Stanley
authors.forename: David J P
authors.initials: DJ
authors.lastname: Ferguson
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Cordell
authors.forename: Veronica J
authors.initials: VJ
authors.lastname: Buckle
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Higgs
authors.forename: William G
authors.initials: WG
authors.lastname: Wood
mesh_terms: D000742:Anemia, Dyserythropoietic, Congenital / Q000235:genetics* / Q000473:pathology*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002843:Chromatin / Q000473:pathology; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000032:analysis*; D004900:Erythroblasts / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006023:Glycoproteins / Q000032:analysis / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009687:Nuclear Proteins; D033921:Vesicular Transport Proteins / Q000032:analysis
chemical_list: C000715594:CBX5 protein, human; C470477:CDAN1 protein, human; D002352:Carrier Proteins; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D006023:Glycoproteins; D009687:Nuclear Proteins; C543353:SEC23B protein, human; D033921:Vesicular Transport Proteins; C560802:codanin-1 protein, mouse; D000090266:Chromobox Protein Homolog 5