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Original research
Genetic and functional insights into CDA-I prevalence and pathogenesis
  1. Aude-Anais Olijnik1,
  2. Noémi B A Roy1,2,3,
  3. Caroline Scott1,
  4. Joseph A Marsh4,
  5. Jill Brown1,
  6. Karin Lauschke5,6,
  7. Katrine Ask5,7,
  8. Nigel Roberts1,
  9. Damien J Downes1,
  10. Sanja Brolih8,
  11. Errin Johnson9,
  12. Barbara Xella1,
  13. Melanie Proven10,
  14. Ria Hipkiss10,
  15. Kate Ryan11,
  16. Per Frisk12,
  17. Johan Mäkk13,
  18. Eva-Lena Maria Stattin14,
  19. Nandini Sadasivam11,
  20. Louisa McIlwaine15,
  21. Quentin A Hill16,
  22. Raffaele Renella17,
  23. Jim R Hughes1,
  24. Richard J Gibbons1,
  25. Anja Groth5,18,
  26. Peter J McHugh8,
  27. Douglas R Higgs1,
  28. Veronica J Buckle1,
  29. Christian Babbs1
  1. 1 MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
  2. 2 Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
  3. 3 NIHR Oxford Biomedical Research Centre and BRC/NHS Translational Molecular Diagnostics Centre, John Radcliffe Hospital, Oxford, UK
  4. 4 MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
  5. 5 Biotech Research and Innovation Centre (BRIC), Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
  6. 6 National Food Institute, Technical University of Denmark, Kongens Lyngby, Denmark
  7. 7 Eli Lilly Danmark, Herlev, Denmark
  8. 8 Department of Oncology, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
  9. 9 Sir William Dunn School of Pathology, University of Oxford, Oxford, UK
  10. 10 Molecular Haematology Laboratory, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
  11. 11 Haematology Department, Manchester University NHS Foundation Trust, Manchester, UK
  12. 12 Department of Women’s and Children’s Health, Uppsala University and Uppsala University Childrens’ Hospital, Uppsala, Sweden
  13. 13 Centre for Health Development, Västmanland Region, Uppsala University, Uppsala, Sweden
  14. 14 Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
  15. 15 Department of Haematology, NHS Trust Greater Glasgow and Clyde, Glasgow, UK
  16. 16 Department of Haematology, St James’s University Hospital, Leeds, UK
  17. 17 Pediatric Hematology-Oncology Laboratory, Lausanne University Hospital and University of Lausanne, Lausanne, VD, Switzerland
  18. 18 The Novo Nordisk Center for Protein Research (CPR), Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
  1. Correspondence to Dr Christian Babbs, MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford, Oxfordshire, UK; christian.babbs{at}


Background Congenital dyserythropoietic anaemia type I (CDA-I) is a hereditary anaemia caused by biallelic mutations in the widely expressed genes CDAN1 and C15orf41. Little is understood about either protein and it is unclear in which cellular pathways they participate.

Methods Genetic analysis of a cohort of patients with CDA-I identifies novel pathogenic variants in both known causative genes. We analyse the mutation distribution and the predicted structural positioning of amino acids affected in Codanin-1, the protein encoded by CDAN1. Using western blotting, immunoprecipitation and immunofluorescence, we determine the effect of particular mutations on both proteins and interrogate protein interaction, stability and subcellular localisation.

Results We identify six novel CDAN1 mutations and one novel mutation in C15orf41 and uncover evidence of further genetic heterogeneity in CDA-I. Additionally, population genetics suggests that CDA-I is more common than currently predicted. Mutations are enriched in six clusters in Codanin-1 and tend to affect buried residues. Many missense and in-frame mutations do not destabilise the entire protein. Rather C15orf41 relies on Codanin-1 for stability and both proteins, which are enriched in the nucleolus, interact to form an obligate complex in cells.

Conclusion Stability and interaction data suggest that C15orf41 may be the key determinant of CDA-I and offer insight into the mechanism underlying this disease. Both proteins share a common pathway likely to be present in a wide variety of cell types; however, nucleolar enrichment may provide a clue as to the erythroid specific nature of CDA-I. The surprisingly high predicted incidence of CDA-I suggests that better ascertainment would lead to improved patient care.

  • molecular genetics
  • cell biology
  • clinical genetics
  • haematology (incl Blood transfusion)

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  • A-AO and NBAR contributed equally.

  • Contributors CB, VJB, DRH and NBR conceived the study and wrote the manuscript. A-AO cultured erythroblasts and performed quantitative western blots in figure 4 and antibody validation. CS cultured erythroblasts and analysed patient mutation data. JAM performed analysis of missense and in frame mutations. KL and KA performed immunoprecipitation and western blots in figure 5. NR performed capture-C from the gene promoters. DJD analysed capture-C, ChIP and ATAC data and generated figure 2. JB cultured patient cells, performed immunofluorescence in figure 5 and commented on the manuscript. SB performed C15orf41 and Codanin-1 antibody validation. EJ performed EM studies in figure 1. BX performed optical mapping studies to identify structural rearrangements in figure 2. MP and RH analysed patient DNA and identified pathogenic mutations shown in figure 1. KR, PF, JM, ES, NS, LMI, QAH, NBR and RR ascertained the CDA-I patients analysed in this paper, provided samples and analysed clinical data. JRH, RG, AG and PJMcH provided supervision, resources and analysed data and commented on the manuscript.

  • Funding This work was supported by MRC (MC_uu_12009), the NationalInstitute for Health Research (NIHR) Oxford Biomedical Research Centre HaematologyTheme at Oxford University Hospitals NHS Trust and University of Oxford and the charitiesBlood Buddies, and the Congenital Anaemia Network. D.J.D. and J.H. were funded by aWellcome Trust Strategic Award (106130/Z/14/Z). EM work was undertaken at the DunnSchool EM Facility. J.M. is supported by an MRC Career Development Award(MR/M02122X/1) and is a Lister Institute Research Prize Fellow.

  • Competing interests JRH is a founder and shareholder of Nucleome Therapeutics.

  • Patient consent for publication Not required.

  • Ethics approval This study was approved by the Wales Research Ethics Committee (REC5) (13/WA/0371) with written consent from patients and/or parents.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available in a public, open access repository. Erythroid sequencing data generated for this work are deposited with the GEO archive (GSE125753). Previously published open-chromatin data sets (GSE86393, GSE75384, GSE115684) were also used.