Recapitulation of erythropoiesis in congenital dyserythropoietic anemia type I (CDA-I) identifies defects in differentiation and nucleolar abnormalities
Caroline Scott,
Damien J. Downes,
Jill M. Brown,
Robert Beagrie,
Aude-Anais Olijnik,
Matthew Gosden,
Ron Schwessinger,
Christopher A. Fisher,
Anna Rose,
David J.P Ferguson,
Errin Johnson,
Quentin A. Hill,
Steven Okoli,
Raffaele Renella,
Kate Ryan,
Marjorie Brand,
Jim Hughes,
Noemi B.A. Roy,
Douglas R. Higgs,
Christian Babbs,
Veronica J. Buckle
Affiliations
Caroline Scott
Weatherall Institute of Molecular Medicine, Oxford University, Oxford
Damien J. Downes
Weatherall Institute of Molecular Medicine, Oxford University, Oxford
Jill M. Brown
Weatherall Institute of Molecular Medicine, Oxford University, Oxford
Robert Beagrie
Weatherall Institute of Molecular Medicine, Oxford University, Oxford
Aude-Anais Olijnik
Weatherall Institute of Molecular Medicine, Oxford University, Oxford
Matthew Gosden
Weatherall Institute of Molecular Medicine, Oxford University, Oxford
Ron Schwessinger
Weatherall Institute of Molecular Medicine, Oxford University, Oxford
Christopher A. Fisher
Weatherall Institute of Molecular Medicine, Oxford University, Oxford
Anna Rose
Weatherall Institute of Molecular Medicine, Oxford University, Oxford
David J.P Ferguson
Ultrastructural Morphology Group, NDCLS, John Radcliffe Hospital, Oxford
Errin Johnson
Sir William Dunn School of Pathology, Oxford University, Oxford
Quentin A. Hill
Leeds Teaching Hospital NHS Trust
Steven Okoli
Imperial College, The Commonwealth Building, The Hammersmith Hospital, Du Cane Rd, London
Raffaele Renella
Pediatric Hematology-Oncology Research Laboratory, CHUV-UNIL Lausanne Switzerland
Kate Ryan
Department of Haematology, Manchester Royal Infirmary, Oxford Rd, Manchester
Marjorie Brand
Sprott Center for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa
Jim Hughes
Weatherall Institute of Molecular Medicine, Oxford University, Oxford
Noemi B.A. Roy
Department of Haematology, Oxford University Hospitals NHS Trust, Churchill Hospital, Old Rd, Headington, and NIHR Biomedical Research Centre, Oxford
Douglas R. Higgs
Weatherall Institute of Molecular Medicine, Oxford University, Oxford
Christian Babbs
Weatherall Institute of Molecular Medicine, Oxford University, Oxford
Veronica J. Buckle
Weatherall Institute of Molecular Medicine, Oxford University, Oxford
The investigation of inherited disorders of erythropoiesis has elucidated many of the principles underlying the production of normal red blood cells and how this is perturbed in human disease. Congenital dyserythropoietic anemia type 1 (CDA-I) is a rare form of anemia caused by mutations in two genes of unknown function: CDAN1 and CDIN1 (previously called C15orf41), whilst in some cases, the underlying genetic abnormality is completely unknown. Consequently, the pathways affected in CDA-I remain to be discovered. In order to enable detailed analysis of this rare disorder we have validated a culture system which recapitulates all of the cardinal hematological features of CDA-I, including the formation of the pathognomonic ‘spongy’ heterochromatin seen by electron microscopy. Using a variety of cell and molecular biological approaches we discovered that erythroid cells in this condition show a delay during terminal erythroid differentiation, associated with increased proliferation and widespread changes in chromatin accessibility. We also show that the proteins encoded by CDAN1 and CDIN1 are enriched in nucleoli which are structurally and functionally abnormal in CDA-I. Together these findings provide important pointers to the pathways affected in CDA-I which for the first time can now be pursued in the tractable culture system utilized here.
